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  • 1.
    Aguilo, Francesca
    et al.
    Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Li, SiDe
    Balasubramaniyan, Natarajan
    Sancho, Ana
    Benko, Sabina
    Zhang, Fan
    Vashisht, Ajay
    Rengasamy, Madhumitha
    Andino, Blanca
    Chen, Chih-hung
    Zhou, Felix
    Qian, Chengmin
    Zhou, Ming-Ming
    Wohlschlegel, James A
    Zhang, Weijia
    Suchy, Frederick J
    Walsh, Martin J
    Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α2016In: Cell Reports, E-ISSN 2211-1247, Vol. 14, no 3, p. 479-492Article in journal (Refereed)
    Abstract [en]

    The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m(5)C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m(5)C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism.

  • 2.
    Birchenough, George M.H.
    et al.
    Department of Medical Biochemistry & Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; Wallenberg Centre for Molecular & Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
    Schröder, Björn
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Sharba, Sinan
    Department of Medical Biochemistry & Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Arike, Liisa
    Department of Medical Biochemistry & Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Recktenwald, Christian V.
    Department of Medical Biochemistry & Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Puértolas Balint, Fabiola
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Subramani, Mahadevan V.
    Department of Medical Biochemistry & Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; Wallenberg Centre for Molecular & Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
    Hansson, Karl T.
    Department of Medical Biochemistry & Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; Wallenberg Centre for Molecular & Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
    Yilmaz, Bahtiyar
    Department for BioMedical Research, University of Bern, Bern, Switzerland.
    Lindén, Sara K.
    Department of Medical Biochemistry & Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Bäckhed, Fredrik
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Hansson, Gunnar C.
    Department of Medical Biochemistry & Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Muc2-dependent microbial colonization of the jejunal mucus layer is diet sensitive and confers local resistance to enteric pathogen infection2023In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 2, article id 112084Article in journal (Refereed)
    Abstract [en]

    Intestinal mucus barriers normally prevent microbial infections but are sensitive to diet-dependent changes in the luminal environment. Here we demonstrate that mice fed a Western-style diet (WSD) suffer regiospecific failure of the mucus barrier in the small intestinal jejunum caused by diet-induced mucus aggregation. Mucus barrier disruption due to either WSD exposure or chromosomal Muc2 deletion results in collapse of the commensal jejunal microbiota, which in turn sensitizes mice to atypical jejunal colonization by the enteric pathogen Citrobacter rodentium. We illustrate the jejunal mucus layer as a microbial habitat, and link the regiospecific mucus dependency of the microbiota to distinctive properties of the jejunal niche. Together, our data demonstrate a symbiotic mucus-microbiota relationship that normally prevents jejunal pathogen colonization, but is highly sensitive to disruption by exposure to a WSD.

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  • 3.
    Boal, Frédéric
    et al.
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    Puhar, Andrea
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). INSERM U1202, Unite´ de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75724 Paris Cedex 15, France.
    Xuereb, Jean-Marie
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    Kunduzova, Oksana
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    Sansonetti, Philippe J.
    INSERM U1202, Unite´ de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75724 Paris Cedex 15, France.
    Payrastre, Bernard
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France; .
    Tronchére, Héléne
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    PI5P Triggers ICAM-1 Degradation in Shigella Infected Cells, Thus Dampening Immune Cell Recruitment2016In: Cell Reports, E-ISSN 2211-1247, Vol. 14, no 4, p. 750-759Article in journal (Refereed)
    Abstract [en]

    Shigella flexneri, the pathogen responsible for bacillary dysentery, has evolved multiple strategies to control the inflammatory response. Here, we show that Shigella subverts the subcellular trafficking of the intercellular adhesion molecule-1 (ICAM-1), a key molecule in immune cell recruitment, in a mechanism dependent on the injected bacterial enzyme IpgD and its product, the lipid mediator PI5P. Overexpression of IpgD, but not a phosphatase dead mutant, induced the internalization and the degradation of ICAM-1 in intestinal epithelial cells. Remarkably, addition of permeant PI5P reproduced IpgD effects and led to the inhibition of neutrophil recruitment. Finally, these results were confirmed in an in vivo model of Shigella infection where IpgD-dependent ICAM-1 internalization reduced neutrophil adhesion. In conclusion, we describe here an immune evasion mechanism used by the pathogen Shigella to divert the host cell trafficking machinery in order to reduce immune cell recruitment.

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  • 4.
    Chin, Chui-Yoke
    et al.
    Emory Antibiotic Resistance Center, Emory University School of Medicine, GA, Atlanta, United States; Emory Vaccine Center, Emory University School of Medicine, GA, Atlanta, United States; Yerkes National Primate Research Center, Emory University School of Medicine, GA, Atlanta, United States; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, GA, Atlanta, United States.
    Zhao, Jinshi
    Department of Biochemistry, Duke University School of Medicine, NC, Durham, United States.
    Llewellyn, Anna C.
    Emory Vaccine Center, Emory University School of Medicine, GA, Atlanta, United States; Yerkes National Primate Research Center, Emory University School of Medicine, GA, Atlanta, United States; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, GA, Atlanta, United States.
    Golovliov, Igor
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Zhou, Pei
    Department of Biochemistry, Duke University School of Medicine, NC, Durham, United States.
    Weiss, David S.
    Emory Antibiotic Resistance Center, Emory University School of Medicine, GA, Atlanta, United States; Emory Vaccine Center, Emory University School of Medicine, GA, Atlanta, United States; Yerkes National Primate Research Center, Emory University School of Medicine, GA, Atlanta, United States; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, GA, Atlanta, United States; Research Service, Atlanta VA Medical Center, GA, Decatur, United States.
    Francisella FlmX broadly affects lipopolysaccharide modification and virulence2021In: Cell Reports, E-ISSN 2211-1247, Vol. 35, no 11, article id 109247Article in journal (Refereed)
    Abstract [en]

    The outer membrane protects Gram-negative bacteria from the host environment. Lipopolysaccharide (LPS), a major outer membrane constituent, has distinct components (lipid A, core, O-antigen) generated by specialized pathways. In this study, we describe the surprising convergence of these pathways through FlmX, an uncharacterized protein in the intracellular pathogen Francisella. FlmX is in the flippase family, which includes proteins that traffic lipid-linked envelope components across membranes. flmX deficiency causes defects in lipid A modification, core remodeling, and O-antigen addition. We find that an F. tularensis mutant lacking flmX is >1,000,000-fold attenuated. Furthermore, FlmX is required to resist the innate antimicrobial LL-37 and the antibiotic polymyxin. Given FlmX's central role in LPS modification and its conservation in intracellular pathogens Brucella, Coxiella, and Legionella, FlmX may represent a novel drug target whose inhibition could cripple bacterial virulence and sensitize bacteria to innate antimicrobials and antibiotics.

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  • 5. Davenne, Tamara
    et al.
    Klintman, Jenny
    Sharma, Sushma
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rigby, Rachel E.
    Blest, Henry T. W.
    Cursi, Chiara
    Bridgeman, Anne
    Dadonaite, Bernadeta
    De Keersmaecker, Kim
    Hillmen, Peter
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Schuh, Anna
    Rehwinkel, Jan
    SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP.2020In: Cell Reports, E-ISSN 2211-1247, Vol. 31, no 6, article id 107640Article in journal (Refereed)
    Abstract [en]

    The anti-leukemia agent forodesine causes cytotoxic overload of intracellular deoxyguanosine triphosphate (dGTP) but is efficacious only in a subset of patients. We report that SAMHD1, a phosphohydrolase degrading deoxyribonucleoside triphosphate (dNTP), protects cells against the effects of dNTP imbalances. SAMHD1-deficient cells induce intrinsic apoptosis upon provision of deoxyribonucleosides, particularly deoxyguanosine (dG). Moreover, dG and forodesine act synergistically to kill cells lacking SAMHD1. Using mass cytometry, we find that these compounds kill SAMHD1-deficient malignant cells in patients with chronic lymphocytic leukemia (CLL). Normal cells and CLL cells from patients without SAMHD1 mutation are unaffected. We therefore propose to use forodesine as a precision medicine for leukemia, stratifying patients by SAMHD1 genotype or expression.

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  • 6. Fuhrmann, Jakob
    et al.
    Mierzwa, Beata
    Trentini, Debora B.
    Spiess, Silvia
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lehner, Anita
    Charpentier, Emmanuelle
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Clausen, Tim
    Structural Basis for Recognizing Phosphoarginine and Evolving Residue-Specific Protein Phosphatases in Gram-Positive Bacteria2013In: Cell Reports, E-ISSN 2211-1247, Vol. 3, no 6, p. 1832-1839Article in journal (Refereed)
    Abstract [en]

    Many cellular pathways are regulated by the competing activity of protein kinases and phosphatases. The recent identification of arginine phosphorylation as a protein modification in bacteria prompted us to analyze the molecular basis of targeting phosphoarginine. In this work, we characterize an annotated tyrosine phosphatase, YwlE, that counteracts the protein arginine kinase McsB. Strikingly, structural studies of YwlE reaction intermediates provide a direct view on a captured arginine residue. Together with biochemical data, the crystal structures depict the evolution of a highly specific phospho-arginine phosphatase, with the use of a size-and-polarity filter for distinguishing phosphorylated arginine from other phosphorylated side chains. To confirm the proposed mechanism, we performed bioinformatic searches for phosphatases, employing a similar selectivity filter, and identified a protein in Drosophila melanogaster exhibiting robust arginine phosphatase activity. In sum, our findings uncover the molecular framework for specific targeting of phospho-arginine and suggest that protein arginine (de) phosphorylation may be relevant in eukaryotes.

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    "Structural Basis for Recognizing Phosphoarginine and Evolving Residue-Specific
  • 7. Galluzzi, Lorenzo
    et al.
    Vitale, Ilio
    Senovilla, Laura
    Olaussen, Ken Andre
    Pinna, Guillaume
    Eisenberg, Tobias
    Goubar, Aicha
    Martins, Isabelle
    Michels, Judith
    Kratassiouk, Gueorgui
    Carmona-Gutierrez, Didac
    Scoazec, Marie
    Vacchelli, Erika
    Schlemmer, Frederic
    Kepp, Oliver
    Shen, Shensi
    Tailler, Maximilien
    Niso-Santano, Mireia
    Morselli, Eugenia
    Criollo, Alfredo
    Adjemian, Sandy
    Jemaa, Mohamed
    Chaba, Kariman
    Pailleret, Claire
    Michaud, Mickael
    Pietrocola, Federico
    Tajeddine, Nicolas
    Rouge, Thibault de La Motte
    Araujo, Natalia
    Morozova, Nadya
    Robert, Thomas
    Ripoche, Hugues
    Commo, Frederic
    Besse, Benjamin
    Validire, Pierre
    Fouret, Pierre
    Robin, Angelique
    Dorvault, Nicolas
    Girard, Philippe
    Gouy, Sebastien
    Pautier, Patricia
    Jaegemann, Nora
    Nickel, Ann-Christin
    Marsili, Sabrina
    Paccard, Caroline
    Servant, Nicolas
    Hupe, Philippe
    Behrens, Carmen
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Kohno, Kimitoshi
    Cremer, Isabelle
    Damotte, Diane
    Alifano, Marco
    Midttun, Oivind
    Ueland, Per Magne
    Lazar, Vladimir
    Dessen, Philippe
    Zischka, Hans
    Chatelut, Etienne
    Castedo, Maria
    Madeo, Frank
    Barillot, Emmanuel
    Thomale, Juergen
    Wistuba, Ignacio Ivan
    Sautes-Fridman, Catherine
    Zitvogel, Laurence
    Soria, Jean-Charles
    Harel-Bellan, Annick
    Kroemer, Guido
    Prognostic Impact of Vitamin B6 Metabolism in Lung Cancer2012In: Cell Reports, E-ISSN 2211-1247, Vol. 2, no 2, p. 257-269Article in journal (Refereed)
    Abstract [en]

    Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.

  • 8. Georgoudaki, Anna-Maria
    et al.
    Prokopec, Kajsa E.
    Boura, Vanessa F.
    Hellqvist, Eva
    Sohn, Silke
    Ostling, Jeanette
    Dahan, Rony
    Harris, Robert A.
    Rantalainen, Mattias
    Klevebring, Daniel
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Brage, Suzanne Egyhazi
    Fuxe, Jonas
    Rolny, Charlotte
    Li, Fubin
    Ravetch, Jeffrey V.
    Karlsson, Mikael C. I.
    Reprogramming Tumor-Associated Macrophages by Antibody Targeting Inhibits Cancer Progression and Metastasis2016In: Cell Reports, E-ISSN 2211-1247, Vol. 15, no 9, p. 2000-2011Article in journal (Refereed)
    Abstract [en]

    Tumors are composed of multiple cell types besides the tumor cells themselves, including innate immune cells such as macrophages. Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells present in the tumor microenvironment (TME). Here, they contribute to immunosuppression, enabling the establishment and persistence of solid tumors as well as metastatic dissemination. We have found that the pattern recognition scavenger receptor MARCO defines a subtype of suppressive TAMs and is linked to clinical outcome. An anti-MARCO monoclonal antibody was developed, which induces anti-tumor activity in breast and colon carcinoma, as well as in melanoma models through reprogramming-TAM-populations to a pro-inflammatory phenotype and increasing tumor immunogenicity. This anti-tumor activity is dependent on the inhibitory Fc-receptor, Fc gamma RIIB, and also enhances the efficacy of checkpoint therapy. These results demonstrate that immunotherapies using antibodies designed to modify myeloid cells of the TME represent a promising mode of cancer treatment.

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  • 9. Gerold, Gisa
    et al.
    Meissner, Felix
    Bruening, Janina
    Welsch, Kathrin
    Perin, Paula M
    Baumert, Thomas F
    Vondran, Florian W
    Kaderali, Lars
    Marcotrigiano, Joseph
    Khan, Abdul G
    Mann, Matthias
    Rice, Charles M
    Pietschmann, Thomas
    Quantitative Proteomics Identifies Serum Response Factor Binding Protein 1 as a Host Factor for Hepatitis C Virus Entry2015In: Cell Reports, E-ISSN 2211-1247, Vol. 12, no 5, p. 864-878, article id S2211-1247(15)00689-0Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) enters human hepatocytes through a multistep mechanism involving, among other host proteins, the virus receptor CD81. How CD81 governs HCV entry is poorly characterized, and CD81 protein interactions after virus binding remain elusive. We have developed a quantitative proteomics protocol to identify HCV-triggered CD81 interactions and found 26 dynamic binding partners. At least six of these proteins promote HCV infection, as indicated by RNAi. We further characterized serum response factor binding protein 1 (SRFBP1), which is recruited to CD81 during HCV uptake and supports HCV infection in hepatoma cells and primary human hepatocytes. SRFBP1 facilitates host cell penetration by all seven HCV genotypes, but not of vesicular stomatitis virus and human coronavirus. Thus, SRFBP1 is an HCV-specific, pan-genotypic host entry factor. These results demonstrate the use of quantitative proteomics to elucidate pathogen entry and underscore the importance of host protein-protein interactions during HCV invasion.

  • 10. Goldberg, Emily L.
    et al.
    Asher, Jennifer L.
    Molony, Ryan D.
    Shaw, Albert C.
    Zeiss, Caroline J.
    Wang, Chao
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Herzog, Raimund I.
    Iwasaki, Akiko
    Dixit, Vishwa Deep
    beta-Hydroxybutyrate deactivates Neutrophil NLRP3 inflammasome to relieve gout flares2017In: Cell Reports, E-ISSN 2211-1247, Vol. 18, no 9, p. 2077-2087Article in journal (Refereed)
    Abstract [en]

    Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1 beta (IL-1 beta) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases beta-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1 beta in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.

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  • 11.
    Hernandez, Sara B.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Dorr, Tobias
    Waldor, Matthew K.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Modulation of Peptidoglycan Synthesis by Recycled Cell Wall Tetrapeptides2020In: Cell Reports, E-ISSN 2211-1247, Vol. 31, no 4, article id 107578Article in journal (Refereed)
    Abstract [en]

    The bacterial cell wall is made of peptidoglycan (PG), a polymer that is essential for the maintenance of cell shape and survival. During growth, bacteria remodel their PG, releasing fragments that are predominantly reinternalized and recycled. Here, we show that Vibrio cholerae recycles PG fragments modified with non-canonical D-amino acids (NCDAA), which lead to the accumulation of cytosolic PG tetrapeptides. We demonstrate that the accumulation of recycled tetrapeptides has two regulatory consequences for the cell wall: reduction of D,D-cross-linkage and reduction of PG synthesis. We further demonstrate that L,D-carboxypeptidases from five different species show a preferential activity for substrates containing canonical (D-alanine) versus non-canonical (D-methionine) D-amino acids, suggesting that the accumulation of intracellular tetrapeptides in NCDAA-rich environments is widespread. Collectively, this work reveals a regulatory role of NCDAA linking PG recycling and synthesis to promote optimal cell wall assembly and composition in the stationary phase.

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  • 12. Hillier, Charles
    et al.
    Pardo, Mercedes
    Yu, Lu
    Bushell, Ellen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sanderson, Theo
    Metcalf, Tom
    Herd, Colin
    Anar, Burcu
    Rayner, Julian C.
    Billker, Oliver
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Choudhary, Jyoti S.
    Landscape of the Plasmodium Interactome Reveals Both Conserved and Species-Specific Functionality2019In: Cell Reports, E-ISSN 2211-1247, Vol. 28, no 6, p. 1635-1647Article in journal (Refereed)
    Abstract [en]

    Malaria represents a major global health issue, and the identification of new intervention targets remains an urgent priority. This search is hampered by more than one-third of the genes of malaria-causing Plasmodium parasites being uncharacterized. We report a large-scale protein interaction network in Plasmodium schizonts, generated by combining blue native-polyacrylamide electrophoresis with quantitative mass spectrometry and machine learning. This integrative approach, spanning 3 species, identifies > 20,000 putative protein interactions, organized into 600 protein clusters. We validate selected interactions, assigning functions in chromatin regulation to previously unannotated proteins and suggesting a role for an EELM2 domain-containing protein and a putative microrchidia protein as mechanistic links between AP2-domain transcription factors and epigenetic regulation. Our interactome represents a high-confidence map of the native organization of core cellular processes in Plasmodium parasites. The network reveals putative functions for uncharacterized proteins, provides mechanistic and structural insight, and uncovers potential alternative therapeutic targets.

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  • 13.
    Holst, Mikkel Roland
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Vidal-Quadras, Maite
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hubert, Madlen
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lundborg, Magnus
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion2017In: Cell Reports, E-ISSN 2211-1247, Vol. 20, no 8, p. 1893-1905Article in journal (Refereed)
    Abstract [en]

    Cellular blebbing, caused by local alterations in cellsurface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrinindependent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension- mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol- interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.

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  • 14.
    Ignatov, Dmitriy
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Vaitkevicius, Karolis
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Durand, Sylvain
    Cahoon, Laty
    Sandberg, Stefanie
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Liu, Xijia
    Kallipolitis, Birgitte H.
    Ryden, Patrik
    Freitag, Nancy
    Condon, Ciaran
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    An mRNA-mRNA Interaction Couples Expression of a Virulence Factor and Its Chaperone in Listeria monocytogenes2020In: Cell Reports, E-ISSN 2211-1247, Vol. 30, no 12, p. 4027-+Article in journal (Refereed)
    Abstract [en]

    Bacterial pathogens often employ RNA regulatory elements located in the 5' untranslated regions (UTRs) to control gene expression. Using a comparative structural analysis, we examine the structure of 5' UTRs at a global scale in the pathogenic bacterium Listeria monocytogenes under different conditions. In addition to discovering an RNA thermoswitch and detecting simultaneous interaction of ribosomes and small RNAs with mRNA, we identify structural changes in the 5' UTR of an mRNA encoding the post-translocation chaperone PrsA2 during infection conditions. We demonstrate that the 5' UTR of the prsA2 mRNA base pairs with the 3' UTR of the full-length hly mRNA encoding listeriolysin O, thus preventing RNase J1-mediated degradation of the prsA2 transcript. Mutants lacking the hly-prsA2 interaction exhibit reduced virulence properties. This work highlights an additional level of RNA regulation, where the mRNA encoding a chaperone is stabilized by the mRNA encoding its substrate.

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  • 15. Invergo, Brandon M.
    et al.
    Brochet, Mathieu
    Yu, Lu
    Choudhary, Jyoti
    Beltrao, Pedro
    Billker, Oliver
    Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
    Sub-minute Phosphoregulation of Cell Cycle Systems during Plasmodium Gamete Formation2017In: Cell Reports, E-ISSN 2211-1247, Vol. 21, no 7, p. 2017-2029Article in journal (Refereed)
    Abstract [en]

    The transmission of malaria parasites to mosquitoes relies on the rapid induction of sexual reproduction upon their ingestion into a blood meal. Haploid female and male gametocytes become activated and emerge from their host cells, and the males enter the cell cycle to produce eight microgametes. The synchronized nature of gametogenesis allowed us to investigate phosphorylation signaling during its first minute in Plasmodium berghei via a high-resolution time course of the phosphoproteome. This revealed an unexpectedly broad response, with proteins related to distinct cell cycle events undergoing simultaneous phosphoregulation. We implicate several protein kinases in the process, and we validate our analyses on the plant-like calcium-dependent protein kinase 4 (CDPK4) and a homolog of serine/arginine-rich protein kinases (SRPK1). Mutants in these kinases displayed distinct phosphoproteomic disruptions, consistent with differences in their phenotypes. The results reveal the central role of protein phosphorylation in the atypical cell cycle regulation of a divergent eukaryote.

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  • 16.
    Johansson, Jarkko
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Nordin, Kristin
    Aging Research Center, Karolinska Institutet & Stockholm University, Tomtebodavägen 18A, Stockholm, Sweden.
    Pedersen, Robin
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Karalija, Nina
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Papenberg, Goran
    Aging Research Center, Karolinska Institutet & Stockholm University, Tomtebodavägen 18A, Stockholm, Sweden.
    Andersson, Micael
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Korkki, Saana M.
    Aging Research Center, Karolinska Institutet & Stockholm University, Tomtebodavägen 18A, Stockholm, Sweden.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Guitart-Masip, Marc
    Aging Research Center, Karolinska Institutet & Stockholm University, Tomtebodavägen 18A, Stockholm, Sweden; Max Planck UCL Centre for Computational Psychiatry and Ageing Research, University College London, London, United Kingdom.
    Rieckmann, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. The Munich Center for the Economics of Aging, Max Planck Institute for Social Law and Social Policy, Munich, Germany.
    Bäckman, Lars
    Aging Research Center, Karolinska Institutet & Stockholm University, Tomtebodavägen 18A, Stockholm, Sweden.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet & Stockholm University, Tomtebodavägen 18A, Stockholm, Sweden.
    Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan2023In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 9, article id 113107Article in journal (Refereed)
    Abstract [en]

    Age-related alterations in D1-like dopamine receptor (D1DR) have distinct implications for human cognition and behavior during development and aging, but the timing of these periods remains undefined. Enabled by a large sample of in vivo assessments (n = 180, age 20 to 80 years of age, 50% female), we discover that age-related D1DR differences pivot at approximately 40 years of age in several brain regions. Focusing on the most age-sensitive dopamine-rich region, we observe opposing pre- and post-forties interrelations among caudate D1DR, cortico-striatal functional connectivity, and memory. Finally, particularly caudate D1DR differences in midlife and beyond, but not in early adulthood, associate with manifestation of white matter lesions. The present results support a model by which excessive dopamine modulation in early adulthood and insufficient modulation in aging are deleterious to brain function and cognition, thus challenging a prevailing view of monotonic D1DR function across the adult lifespan.

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  • 17. Kamps, Dominic
    et al.
    Koch, Johannes
    Juma, Victor O.
    Campillo-Funollet, Eduard
    Graessl, Melanie
    Banerjee, Soumya
    Mazel, Tomas
    Chen, Xi
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Chemical Genomics Centre of the Max-Planck Society, Dortmund, Germany.
    Portet, Stephanie
    Madzvamuse, Anotida
    Nalbant, Perihan
    Dehmelt, Leif
    Optogenetic Tuning Reveals Rho Amplification-Dependent Dynamics of a Cell Contraction Signal Network2020In: Cell Reports, E-ISSN 2211-1247, Vol. 33, no 9, article id 108467Article in journal (Refereed)
    Abstract [en]

    Local cell contraction pulses play important roles in tissue and cell morphogenesis. Here, we improve a chemo-optogenetic approach and apply it to investigate the signal network that generates these pulses. We use these measurements to derive and parameterize a system of ordinary differential equations describing temporal signal network dynamics. Bifurcation analysis and numerical simulations predict a strong dependence of oscillatory system dynamics on the concentration of GEF-H1, an Lbc-type RhoGEF, which mediates the positive feedback amplification of Rho activity. This prediction is confirmed experimentally via optogenetic tuning of the effective GEF-H1 concentration in individual living cells. Numerical simulations show that pulse amplitude is most sensitive to external inputs into the myosin component at low GEF-H1 concentrations and that the spatial pulse width is dependent on GEF-H1 diffusion. Our study offers a theoretical framework to explain the emergence of local cell contraction pulses and their modulation by biochemical and mechanical signals.

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  • 18. Krypotou, Emilia
    et al.
    Scortti, Mariela
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Oelker, Melanie
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Luisi, Ben F.
    Sauer-Eriksson, A. Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Vazquez-Boland, Jose
    Control of Bacterial Virulence through the Peptide Signature of the Habitat2019In: Cell Reports, E-ISSN 2211-1247, Vol. 26, no 7, p. 1815-1827Article in journal (Refereed)
    Abstract [en]

    To optimize fitness, pathogens selectively activate their virulence program upon host entry. Here, we report that the facultative intracellular bacterium Listeria monocytogenes exploits exogenous oligopeptides, a ubiquitous organic N source, to sense the environment and control the activity of its virulence transcriptional activator, PrfA. Using a genetic screen in adsorbent- treated ( PrfA-inducing) medium, we found that PrfA is functionally regulated by the balance between activating and inhibitory nutritional peptides scavenged via the Opp transport system. Activating peptides provide essential cysteine precursor for the PrfA-inducing cofactor glutathione ( GSH). Non-cysteine-containing peptides cause promiscuous PrfA inhibition. Biophysical and co-crystallization studies reveal that peptides inhibit PrfA through steric blockade of the GSH binding site, a regulation mechanism directly linking bacterial virulence and metabolism. L. monocytogenes mutant analysis in macrophages and our functional data support a model in which changes in the balance of antagonistic Oppimported oligopeptides promote PrfA induction intra-cellularly and PrfA repression outside the host.

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  • 19.
    Kuzhandaivel, Anujaianthi
    et al.
    Linköpings universitet, Avdelningen för cellbiologi.
    Schultz, Sebastian W.
    Linköpings universitet, Avdelningen för cellbiologi.
    Alkhori, Liza
    Linköpings universitet, Avdelningen för cellbiologi.
    Alenius, Mattias
    Linköpings universitet, Avdelningen för cellbiologi.
    Cilia-Mediated Hedgehog Signaling in Drosophila2014In: Cell Reports, E-ISSN 2211-1247, Vol. 7, no 3, p. 672-680Article in journal (Refereed)
    Abstract [en]

    Cilia mediate Hedgehog (Hh) signaling in vertebrates and Hh deregulation results in several clinical manifestations, such as obesity, cognitive disabilities, developmental malformations, and various cancers. Drosophila cells are nonciliated during development, which has led to the assumption that cilia-mediated Hh signaling is restricted to vertebrates. Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. We show that Cos2 and Fused are required for the ciliary transport of Smoothened and that cilia mediate the expression of the Hh pathway target genes. Taken together, our data demonstrate that Hh signaling in Drosophila can be mediated by two pathways and that the ciliary Hh pathway is conserved from Drosophila to vertebrates.

  • 20. Leitner, Johannes
    et al.
    Retzer, Katarzyna
    Malenica, Nenad
    Bartkeviciute, Rasa
    Lucyshyn, Doris
    Jäger, Gunilla
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Korbei, Barbara
    Byström, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Luschnig, Christian
    Meta-regulation of Arabidopsis Auxin Responses Depends on tRNA Maturation2015In: Cell Reports, E-ISSN 2211-1247, Vol. 11, no 4, p. 516-526Article in journal (Refereed)
    Abstract [en]

    Polar transport of the phytohormone auxin throughout plants shapes morphogenesis and is subject to stringent and specific control. Here, we identify basic cellular activities connected to translational control of gene expression as sufficient to specify auxin-mediated development. Mutants in subunits of Arabidopsis Elongator, a protein complex modulating translational efficiency via maturation of tRNAs, exhibit defects in auxin-controlled developmental processes, associated with reduced abundance of PIN-formed (PIN) auxin transport proteins. Similar anomalies are observed upon interference with tRNA splicing by downregulation of RNA ligase (AtRNL), pointing to a general role of tRNA maturation in auxin signaling. Elongator Protein 6 (ELP6) and AtRNL expression patterns underline an involvement in adjusting PIN protein levels, whereas rescue of mutant defects by auxin indicates rate-limiting activities in auxin-controlled organogenesis. This emphasizes mechanisms in which auxin serves as a bottleneck for plant morphogenesis, translating common cellular activities into defined developmental readouts.

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  • 21. Liew, Li Phing
    et al.
    Lim, Zun Yi
    Cohen, Matan
    Kong, Ziqing
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Marjavaara, Lisette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bell, Stephen D
    Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase2016In: Cell Reports, E-ISSN 2211-1247, Vol. 17, no 6, p. 1657-1670Article in journal (Refereed)
    Abstract [en]

    In many organisms, hydroxyurea (HU) inhibits class I ribonucleotide reductase, leading to lowered cellular pools of deoxyribonucleoside triphosphates. The reduced levels for DNA precursors is believed to cause replication fork stalling. Upon treatment of the hyperthermophilic archaeon Sulfolobus solfataricus with HU, we observe dose-dependent cell cycle arrest, accumulation of DNA double-strand breaks, stalled replication forks, and elevated levels of recombination structures. However, Sulfolobus has a HU-insensitive class II ribonucleotide reductase, and we reveal that HU treatment does not significantly impact cellular DNA precursor pools. Profiling of protein and transcript levels reveals modulation of a specific subset of replication initiation and cell division genes. Notably, the selective loss of the regulatory subunit of the primase correlates with cessation of replication initiation and stalling of replication forks. Furthermore, we find evidence for a detoxification response induced by HU treatment.

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  • 22.
    Martin, Océane C.B.
    et al.
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Bergonzini, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lopez Chiloeches, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Paparouna, Eleni
    Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
    Butter, Deborah
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Theodorou, Sofia D.P.
    Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
    Haykal, Maria M.
    Université Paris-Saclay, Institut Gustave Roussy, Inserm U981, Biomarqueurs prédictifs et nouvelles stratégies thérapeutiques en oncologie, Villejuif, France.
    Boutet-Robinet, Elisa
    Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France.
    Tebaldi, Toma
    Center for Biomedical Data Science, Yale School of Medicine, CT, New Haven, United States.
    Wakeham, Andrew
    The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, University of Toronto, ON, Toronto, Canada.
    Rhen, Mikael
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Gorgoulis, Vassilis G.
    Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation, Academy of Athens, Athens, Greece; Institute for Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom; Manchester Centre for Cellular Metabolism, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
    Mak, Tak
    The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, University of Toronto, ON, Toronto, Canada.
    Pateras, Ioannis S.
    Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
    Frisan, Teresa
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Influence of the microenvironment on modulation of the host response by typhoid toxin2021In: Cell Reports, E-ISSN 2211-1247, Vol. 35, no 1, article id 108931Article in journal (Refereed)
    Abstract [en]

    Bacterial genotoxins cause DNA damage in eukaryotic cells, resulting in activation of the DNA damage response (DDR) in vitro. These toxins are produced by Gram-negative bacteria, enriched in the microbiota of inflammatory bowel disease (IBD) and colorectal cancer (CRC) patients. However, their role in infection remains poorly characterized. We address the role of typhoid toxin in modulation of the host-microbial interaction in health and disease. Infection with a genotoxigenic Salmonella protects mice from intestinal inflammation. We show that the presence of an active genotoxin promotes DNA fragmentation and senescence in vivo, which is uncoupled from an inflammatory response and unexpectedly associated with induction of an anti-inflammatory environment. The anti-inflammatory response is lost when infection occurs in mice with acute colitis. These data highlight a complex context-dependent crosstalk between bacterial-genotoxin-induced DDR and the host immune response, underlining an unexpected role for bacterial genotoxins.

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  • 23.
    Mathiasen, Sarah L.
    et al.
    LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
    Gall-Mas, Laura
    LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
    Pateras, Ioannis S.
    Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, Athens, Greece.
    Theodorou, Sofia D.P.
    Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, Athens, Greece.
    Namini, Martin R.J.
    LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
    Hansen, Morten B.
    Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Martin, Océane C.B.
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Vadivel, Chella Krishna
    LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
    Ntostoglou, Konstantinos
    Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, Athens, Greece.
    Butter, Deborah
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Givskov, Michael
    Costerton Biofilm Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
    Geisler, Carsten
    LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
    Akbar, Arne N.
    Division of Medicine, University College London, London, United Kingdom.
    Gorgoulis, Vassilis G.
    Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
    Frisan, Teresa
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Ødum, Niels
    LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
    Krejsgaard, Thorbjørn
    LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
    Bacterial genotoxins induce T cell senescence2021In: Cell Reports, E-ISSN 2211-1247, Vol. 35, no 10, article id 109220Article in journal (Refereed)
    Abstract [en]

    Several types of pathogenic bacteria produce genotoxins that induce DNA damage in host cells. Accumulating evidence suggests that a central function of these genotoxins is to dysregulate the host's immune response, but the underlying mechanisms remain unclear. To address this issue, we investigated the effects of the most widely expressed bacterial genotoxin, the cytolethal distending toxin (CDT), on T cells—the key mediators of adaptive immunity. We show that CDT induces premature senescence in activated CD4 T cells in vitro and provide evidence suggesting that infection with genotoxin-producing bacteria promotes T cell senescence in vivo. Moreover, we demonstrate that genotoxin-induced senescent CD4 T cells assume a senescence-associated secretory phenotype (SASP) which, at least partly, is orchestrated by the ATM-p38 signaling axis. These findings provide insight into the immunomodulatory properties of bacterial genotoxins and uncover a putative link between bacterial infections and T cell senescence.

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  • 24. Nehme, Ralda
    et al.
    Zuccaro, Emanuela
    Ghosh, Sulagna Dia
    Li, Chenchen
    Sherwood, John L.
    Pietilainen, Olli
    Barrett, Lindy E.
    Limone, Francesco
    Worringer, Kathleen A.
    Kommineni, Sravya
    Zang, Ying
    Cacchiarelli, Davide
    Meissner, Alex
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Haggarty, Stephen
    Madison, Jon
    Muller, Matthias
    Arlotta, Paola
    Fu, Zhanyan
    Feng, Guoping
    Eggan, Kevin
    Combining NGN2 Programming with Developmental Patterning Generates Human Excitatory Neurons with NMDAR-Mediated Synaptic Transmission2018In: Cell Reports, E-ISSN 2211-1247, Vol. 23, no 8, p. 2509-2523Article in journal (Refereed)
    Abstract [en]

    Transcription factor programming of pluripotent stem cells (PSCs) has emerged as an approach to generate human neurons for disease modeling. However, programming schemes produce a variety of cell types, and those neurons that are made often retain an immature phenotype, which limits their utility in modeling neuronal processes, including synaptic transmission. We report that combining NGN2 programming with SMAD and WNT inhibition generates human patterned induced neurons (hpiNs). Single-cell analyses showed that hpiN cultures contained cells along a developmental continuum, ranging from poorly differentiated neuronal progenitors to well-differentiated, excitatory glutamatergic neurons. The most differentiated neurons could be identified using a CAMK2A::GFP reporter gene and exhibited greater functionality, including NMDAR-mediated synaptic transmission. We conclude that utilizing single-cell and reporter gene approaches for selecting successfully programmed cells for study will greatly enhance the utility of hpiNs and other programmed neuronal populations in the modeling of nervous system disorders.

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  • 25. Prigge, Justin R.
    et al.
    Coppo, Lucia
    Martin, Sebastin S.
    Ogata, Fernando
    Miller, Colin G.
    Bruschwein, Michael D.
    Orlicky, David J.
    Shearn, Colin T.
    Kundert, Jean A.
    Lytchier, Julia
    Herr, Alix E.
    Mattsson, Åse
    Taylor, Matthew P.
    Gustafsson, Tomas N.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Arnér, Elias S. J.
    Holmgren, Arne
    Schmidt, Edward E.
    Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase2017In: Cell Reports, E-ISSN 2211-1247, Vol. 19, no 13, p. 2771-2781Article in journal (Refereed)
    Abstract [en]

    Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP(+) ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed. Here, we show that liver-specific co-disruption of the genes encoding Trx1, TrxR1, and Gsr (triplenull) causes dramatic hepatocyte hyperproliferation. Thus, even in the absence of Trx1, methionine-fueled glutathione production supports hepatocyte S phase deoxyribonucleotide production. Also, Trx1 in the absence of TrxR1 provides a survival advantage to cells under hyperglycemic stress, suggesting that glutathione, likely via glutaredoxins, can reduce Trx1 disulfide in vivo. In triple-null livers like in many cancers, deoxyribonucleotide synthesis places a critical yet relatively low-volume demand on these reductase systems, thereby favoring high hepatocyte turnover over sustained hepatocyte integrity.

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  • 26.
    Sanchez, Gonzalo Manuel
    et al.
    Linköpings universitet, Avdelningen för cellbiologi.
    Alkhori Franzén, Liza
    Linköpings universitet, Avdelningen för cellbiologi.
    Hatano, Eduardo
    Linköpings universitet, Avdelningen för cellbiologi.
    Schultz, Sebastian
    Linköpings universitet, Avdelningen för cellbiologi.
    Kuzhandaivel, Anujaianthi
    Linköpings universitet, Institutionen för klinisk och experimentell medicin.
    Jafari, Shadi
    Linköpings universitet, Avdelningen för cellbiologi.
    Granseth, Björn
    Linköpings universitet, Avdelningen för cellbiologi.
    Alenius, Mattias
    Linköpings universitet, Avdelningen för cellbiologi.
    Hedgehog Signaling Regulates the Ciliary Transport of Odorant Receptors in Drosophila2016In: Cell Reports, E-ISSN 2211-1247, Vol. 14, no 3, p. 464-470Article in journal (Refereed)
    Abstract [en]

    Hedgehog (Hh) signaling is a key regulatory pathway during development and also has a functional role in mature neurons. Here, we show that Hh signaling regulates the odor response in adult Drosophila olfactory sensory neurons (OSNs). We demonstrate that this is achieved by regulating odorant receptor (OR) transport to and within the primary cilium in OSN neurons. Regulation relies on ciliary localization of the Hh signal transducer Smoothened (Smo). We further demonstrate that the Hh- and Smo-dependent regulation of the kinesin-like protein Cos2 acts in parallel to the intraflagellar transport system (IFT) to localize ORs within the cilium compartment. These findings expand our knowledge of Hh signaling to encompass chemosensory modulation and receptor trafficking.

  • 27.
    Schwartz, Yuri B.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pirrotta, Vincenzo
    Ruled by ubiquitylation: a new order for Polycomb recruitment2014In: Cell Reports, E-ISSN 2211-1247, Vol. 8, no 2, p. 321-325Article in journal (Refereed)
    Abstract [en]

    Polycomb complexes are found in most cells, but they must be targeted to specific genes in specific cell types in order to regulate pluripotency and differentiation. The recruitment of Polycomb complexes to specific targets has been widely thought to occur in two steps: first, one complex, PRC2, produces histone H3 lysine 27 (H3K27) trimethylation at a specific gene, and then the PRC1 complex is recruited by its ability to bind to H3K27me3. Now, three new articles turn this model upside-down by showing that binding of a variant PRC1 complex and subsequent H2A ubiquitylation of surrounding chromatin is sufficient to trigger the recruitment of PRC2 and H3K27 trimethylation. These studies also show that ubiquitylated H2A is directly sensed by PRC2 and that ablation of PRC1-mediated H2A ubiquitylation impairs genome-wide PRC2 binding and disrupts mouse development.

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  • 28. Siegrist, M. Sloan
    et al.
    Aditham, Arjun K.
    Espaillat, Akbar
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Cameron, Todd A.
    Whiteside, Sarah A.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Portnoy, Daniel A.
    Bertozzi, Carolyn R.
    Host Actin Polymerization Tunes the Cell Division Cycle of an Intracellular Pathogen2015In: Cell Reports, E-ISSN 2211-1247, Vol. 11, no 4, p. 499-507Article in journal (Refereed)
    Abstract [en]

    Growth and division are two of the most fundamental capabilities of a bacterial cell. While they are well described for model organisms growing in broth culture, very little is known about the cell division cycle of bacteria replicating in more complex environments. Using a D-alanine reporter strategy, we found that intracellular Listeria monocytogenes (Lm) spend a smaller proportion of their cell cycle dividing compared to Lm growing in broth culture. This alteration to the cell division cycle is independent of bacterial doubling time. Instead, polymerization of host-derived actin at the bacterial cell surface extends the non-dividing elongation period and compresses the division period. By decreasing the relative proportion of dividing Lm, actin polymerization biases the population toward cells with the highest propensity to form actin tails. Thus, there is a positive-feedback loop between the Lm cell division cycle and a physical interaction with the host cytoskeleton.

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  • 29. Sola-Riera, Caries
    et al.
    Gupta, Shawon
    Maleki, Kimia T.
    Gonzalez-Rodriguez, Patricia
    Saidi, Dale
    Zimmer, Christine L.
    Vangeti, Sindhu
    Rivino, Laura
    Leo, Yee-Sin
    Lye, David Chien
    MacAry, Paul A.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Smed-Sorensen, Anna
    Joseph, Bertrand
    Bjorkstrom, Niklas K.
    Ljunggren, Hans-Gustaf
    Klingstrom, Jonas
    Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 52019In: Cell Reports, E-ISSN 2211-1247, Vol. 28, no 8, p. 2124-2139Article in journal (Refereed)
    Abstract [en]

    Cytotoxic lymphocytes normally kill virus-infected cells by apoptosis induction. Cytotoxic granule-dependent apoptosis induction engages the intrinsic apoptosis pathway, whereas death receptor (DR)-dependent apoptosis triggers the extrinsic apoptosis pathway. Hantaviruses, single-stranded RNA viruses of the order Bunyavirales, induce strong cytotoxic lymphocyte responses in infected humans. Cytotoxic lymphocytes, however, are largely incapable of eradicating hantavirus-infected cells. Here, we show that the prototypic hantavirus, Hantaan virus (HTNV), induces TRAIL production but strongly inhibits TRAIL-mediated extrinsic apoptosis induction in infected cells by downregulating DR5 cell surface expression. Mechanistic analyses revealed that HTNV triggers both 26S proteasome-dependent degradation of DR5 through direct ubiquitination of DR5 and hampers DR5 transport to the cell surface. These results corroborate earlier findings, demonstrating that hantavirus also inhibits cytotoxic cell granule-dependent apoptosis induction. Together, these findings show that HTNV counteracts intrinsic and extrinsic apoptosis induction pathways, providing a defense mechanism utilized by hantaviruses to inhibit cytotoxic cell-mediated eradication of infected cells.

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  • 30. Starosta, Agata L
    et al.
    Lassak, Jürgen
    Peil, Lauri
    Atkinson, Gemma C
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute of Technology, University of Tartu, Tartu 50090, Estonia.
    Woolstenhulme, Christopher J.
    Virumäe, Kai
    Buskirk, Allen
    Tenson, Tanel
    Remme, Jaanus
    Jung, Kirsten
    Wilson, Daniel N.
    A conserved proline triplet in Val-tRNA synthetase and the origin of elongation factor P2014In: Cell Reports, E-ISSN 2211-1247, Vol. 9, no 2, p. 476-483Article in journal (Refereed)
    Abstract [en]

    Bacterial ribosomes stall on polyproline stretches and require the elongation factor P (EF-P) to relieve the arrest. Yet it remains unclear why evolution has favored the development of EF-P rather than selecting against the occurrence of polyproline stretches in proteins. We have discovered that only a single polyproline stretch is invariant across all domains of life, namely a proline triplet in ValS, the tRNA synthetase, that charges tRNA(Val) with valine. Here, we show that expression of ValS in vivo and in vitro requires EF-P and demonstrate that the proline triplet located in the active site of ValS is important for efficient charging of tRNA(Val) with valine and preventing formation of mischarged Thr-tRNA(Val) as well as efficient growth of E. coli in vivo. We suggest that the critical role of the proline triplet for ValS activity may explain why bacterial cells coevolved the EF-P rescue system.

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  • 31.
    Tadala, Lalitha
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Langenbach, Dorothee
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Dannborg, Mirjam
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cervantes-Rivera, Ramón
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sharma, Atin
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Vieth, Kevin
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Rieckmann, Lisa M.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wanders, Alkwin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Cisneros, David A.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Puhar, Andrea
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Infection-induced membrane ruffling initiates danger and immune signaling via the mechanosensor PIEZO12022In: Cell Reports, E-ISSN 2211-1247, Vol. 40, no 6, article id 111173Article in journal (Refereed)
    Abstract [en]

    Microorganisms are generally sensed by receptors recognizing microbial molecules, which evoke changes in cellular activities and gene expression. Bacterial pathogens induce secretion of the danger signal ATP as an early alert response of intestinal epithelial cells, initiating overt inflammation. However, what triggers ATP secretion during infection is unclear. Here we show that the inherently mechanosensitive plasma membrane channel PIEZO1 acts as a sensor for bacterial entry. PIEZO1 is mechanically activated by invasion-induced membrane ruffles upstream of Ca2+ influx and ATP secretion. Mimicking mechanical stimuli of pathogen uptake with sterile beads equally elicits ATP secretion. Chemical or genetic PIEZO1 inactivation inhibits mechanically induced ATP secretion. Moreover, chemical or mechanical PIEZO1 activation evokes gene expression in immune and barrier pathways. Thus, mechanosensation of invasion-induced plasma membrane distortion initiates immune signaling upon infection, independently of detection of microbial molecules. Hence, PIEZO1-dependent detection of infection is driven by physical signals instead of chemical ligands.

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  • 32. Tosal-Castano, Sergi
    et al.
    Peselj, Carlotta
    Kohler, Verena
    Department of Molecular Biosciences, The Wenner-Gren Institute, StockholmUniversity, Stockholm, Sweden.
    Habernig, Lukas
    Berglund, Lisa Larsson
    Ebrahimi, Mahsa
    Vögtle, F.-Nora
    Höög, Johanna
    Andréasson, Claes
    Büttner, Sabrina
    Snd3 controls nucleus-vacuole junctions in response to glucose signaling2021In: Cell Reports, E-ISSN 2211-1247, Vol. 34, no 3, article id 108637Article in journal (Refereed)
    Abstract [en]

    Membrane contact sites facilitate the exchange of metabolites between organelles to support interorganellar communication. The nucleus-vacuole junctions (NVJs) establish physical contact between the perinuclear endoplasmic reticulum (ER) and the vacuole. Although the NVJ tethers are known, how NVJ abundance and composition are controlled in response to metabolic cues remains elusive. Here, we identify the ER protein Snd3 as central factor for NVJ formation. Snd3 interacts with NVJ tethers, supports their targeting to the contacts, and is essential for NVJ formation. Upon glucose exhaustion, Snd3 relocalizes from the ER to NVJs and promotes contact expansion regulated by central glucose signaling pathways. Glucose replenishment induces the rapid dissociation of Snd3 from the NVJs, preceding the slow disassembly of the junctions. In sum, this study identifies a key factor required for formation and regulation of NVJs and provides a paradigm for metabolic control of membrane contact sites.

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  • 33.
    Tsioras, Konstantinos
    et al.
    The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States.
    Smith, Kevin C.
    The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States.
    Edassery, Seby L.
    The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States.
    Garjani, Mehraveh
    The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States.
    Li, Yichen
    Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, CA, Los Angeles, United States.
    Williams, Chloe
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    McKenna, Elizabeth D.
    The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States.
    Guo, Wenxuan
    Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, CA, Los Angeles, United States.
    Wilen, Anika P.
    The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States.
    Hark, Timothy J.
    The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ostrow, Lyle W.
    Department of Neurology, Lewis Katz School of Medicine at Temple University, PA, Philadelphia, United States.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Ichida, Justin K.
    Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, CA, Los Angeles, United States.
    Kalb, Robert G.
    The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States.
    Savas, Jeffrey N.
    The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States.
    Kiskinis, Evangelos
    The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, IL, Chicago, United States; Simpson Querrey Institute, Northwestern University, IL, Chicago, United States; Department of Neuroscience, Northwestern University Feinberg School of Medicine, IL, Chicago, United States.
    Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis2023In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 10, article id 113160Article in journal (Refereed)
    Abstract [en]

    Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs. The interactome of VCP is altered in mutSOD1 MNs in vitro, while VCP selectively accumulates in the affected motor cortex of ALS-SOD1 patients. Overexpression of VCP rescues mutSOD1 toxicity in MNs in vitro and in a C. elegans model in vivo, in part due to its ability to modulate the degradation of insoluble mutSOD1. Our results demonstrate that VCP contributes to mutSOD1-dependent degeneration, link two distinct ALS-causal genes, and highlight selective protein degradation impairment in ALS pathophysiology.

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  • 34.
    Zhao, Yunpo
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Emilia
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Duan, Jianli
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Han, Zhe
    Center for Precision Disease Modeling, University of Maryland School of Medicine, MD, Baltimore, United States.
    Alenius, Mattias
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Fat- and sugar-induced signals regulate sweet and fat taste perception in Drosophila2023In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 11, article id 113387Article in journal (Refereed)
    Abstract [en]

    In this study, we investigate the interplay between taste perception and macronutrients. While sugar's and protein's self-regulation of taste perception is known, the role of fat remains unclear. We reveal that in Drosophila, fat overconsumption reduces fatty acid taste in favor of sweet perception. Conversely, sugar intake increases fatty acid perception and suppresses sweet taste. Genetic investigations show that the sugar signal, gut-secreted Hedgehog, suppresses sugar taste and enhances fatty acid perception. Fat overconsumption induces unpaired 2 (Upd2) secretion from adipose tissue to the hemolymph. We reveal taste neurons take up Upd2, which triggers Domeless suppression of fatty acid perception. We further show that the downstream JAK/STAT signaling enhances sweet perception and, via Socs36E, fine-tunes Domeless activity and the fatty acid taste perception. Together, our results show that sugar regulates Hedgehog signaling and fat induces Upd2 signaling to balance nutrient intake and to regulate sweet and fat taste perception.

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