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  • 1.
    Corkery, Dale
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Castro-Gonzalez, Sergio
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Knyazeva, Anastasia
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Herzog, Laura K.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    An ATG12-ATG5-TECPR1 E3-like complex regulates unconventional LC3 lipidation at damaged lysosomes2023In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 24, no 9, article id e56841Article in journal (Refereed)
    Abstract [en]

    Lysosomal membrane damage represents a threat to cell viability. As such, cells have evolved sophisticated mechanisms to maintain lysosomal integrity. Small membrane lesions are detected and repaired by the endosomal sorting complex required for transport (ESCRT) machinery while more extensively damaged lysosomes are cleared by a galectin-dependent selective macroautophagic pathway (lysophagy). In this study, we identify a novel role for the autophagosome-lysosome tethering factor, TECPR1, in lysosomal membrane repair. Lysosomal damage promotes TECPR1 recruitment to damaged membranes via its N-terminal dysferlin domain. This recruitment occurs upstream of galectin and precedes the induction of lysophagy. At the damaged membrane, TECPR1 forms an alternative E3-like conjugation complex with the ATG12-ATG5 conjugate to regulate ATG16L1-independent unconventional LC3 lipidation. Abolishment of LC3 lipidation via ATG16L1/TECPR1 double knockout impairs lysosomal recovery following damage.

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  • 2.
    Corkery, Dale
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nadeem, Aftab
    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).
    Aung, Kyaw Min
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Hassan, Ahmed
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Liu, Tao
    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).
    Lystad, Alf Håkon
    Wang, Hui
    Persson, Karina
    Umeå University, Faculty of Science and Technology, Department of Chemistry. 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).
    Simonsen, Anne
    Uhlin, Bernt Eric
    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).
    Wai, Sun Nyunt
    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).
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Vibrio cholerae cytotoxin MakA induces noncanonical autophagy resulting in the spatial inhibition of canonical autophagy2021In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 134, no 5, article id jcs252015Article in journal (Refereed)
    Abstract [en]

    Autophagy plays an essential role in the defense against manymicrobial pathogens as a regulator of both innate and adaptive immunity. Some pathogens have evolved sophisticated mechanisms that promote their ability to evade or subvert host autophagy. Here, we describe a novel mechanism of autophagy modulation mediated by the recently discovered Vibrio cholerae cytotoxin, motility-associatedkilling factor A (MakA). pH-dependent endocytosis of MakA by host cells resulted in the formation of a cholesterol-rich endolysosomal membrane aggregate in the perinuclear region. Aggregate formation induced the noncanonical autophagy pathway driving unconventional LC3 (herein referring to MAP1LC3B) lipidation on endolysosomal membranes. Subsequent sequestration of the ATG12-ATG5-ATG16L1 E3-like enzyme complex, required for LC3 lipidation at the membranous aggregate, resulted in an inhibition of both canonical autophagy and autophagy-related processes, including the unconventional secretion of interleukin-1β (IL-1β). These findings identify a novel mechanismof host autophagy modulation and immune modulation employed by V. cholerae during bacterial infection.

  • 3.
    Corkery, Dale P.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    ATG12–ATG5-TECPR1: an alternative E3-like complex utilized during the cellular response to lysosomal membrane damage2024In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 20, no 2, p. 443-444Article in journal (Refereed)
    Abstract [en]

    ATG16L1 is an essential component of the Atg8-family protein conjugation machinery, providing membrane targeting for the ATG12–ATG5 conjugate. Recently, we identified an alternative E3-like complex that functions independently of ATG16L1. This complex utilizes the autophagosome-lysosome tethering factor TECPR1 for membrane targeting. TECPR1 is recruited to damaged lysosomal membranes via a direct interaction with sphingomyelin. At the damaged membrane, TECPR1 assembles into an E3-like complex with ATG12–ATG5 to regulate unconventional LC3 lipidation and promote efficient lysosomal repair.

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  • 4.
    Corkery, Dale P.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Eating while intoxicated: characterizing the molecular mechanism behind V. cholerae toxin MakA-regulated autophagy2023In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 19, no 6, p. 1885-1886Article in journal (Refereed)
    Abstract [en]

    Extracellular pathogens utilize secreted virulence factors to regulate host cell function. Recently we characterized the molecular mechanism behind host macroautophagy/autophagy regulation by the Vibrio cholerae toxin MakA. Cholesterol binding at the plasma membrane induces MakA endocytosis and pH-dependent pore assembly. Membrane perforation of late endosomal membranes induces cellular membrane repair pathways and V-ATPase-dependent unconventional LC3 lipidation on damaged membranes.

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  • 5.
    Corkery, Dale
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Ursu, Andrei
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, Germany.
    Lucas, Belén
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, Germany.
    Grigalunas, Michael
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, Germany.
    Kriegler, Simon
    Physical Chemistry I – Biophysical Chemistry, Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany, Germany.
    Oliva, Rosario
    Physical Chemistry I – Biophysical Chemistry, Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany, Germany; Department of Chemical Sciences, University of Naples Federico II, Via Cintia 4, Naples, Italy.
    Dec, Robert
    Physical Chemistry I – Biophysical Chemistry, Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany, Germany.
    Koska, Sandra
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, Germany.
    Pahl, Axel
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, Germany.
    Sievers, Sonja
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, Germany.
    Ziegler, Slava
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, Germany.
    Winter, Roland
    Physical Chemistry I – Biophysical Chemistry, Department of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany, Germany.
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Waldmann, Herbert
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, Dortmund, Germany; Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Strasse 6, Dortmund, Germany.
    Inducin triggers LC3-lipidation and ESCRT-mediated lysosomal membrane repair2023In: ChemBioChem, ISSN 1439-4227, E-ISSN 1439-7633, Vol. 24, no 24, article id e202300579Article in journal (Refereed)
    Abstract [en]

    Lipidation of the LC3 protein has frequently been employed as a marker of autophagy. However, LC3-lipidation is also triggered by stimuli not related to canonical autophagy. Therefore, characterization of the driving parameters for LC3 lipidation is crucial to understanding the biological roles of LC3. We identified a pseudo-natural product, termed Inducin, that increases LC3 lipidation independently of canonical autophagy, impairs lysosomal function and rapidly recruits Galectin 3 to lysosomes. Inducin treatment promotes Endosomal Sorting Complex Required for Transport (ESCRT)-dependent membrane repair and transcription factor EB (TFEB)-dependent lysosome biogenesis ultimately leading to cell death.

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  • 6.
    Corkery, Dale
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Dowaidar, Moataz
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)2021In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 17, no 1, p. 1-382Article in journal (Refereed)
    Abstract [en]

    In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

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  • 7. Foley, Daniel J.
    et al.
    Zinken, Sarah
    Corkery, Dale
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Laraia, Luca
    Pahl, Axel
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Waldmann, Herbert
    Phenotyping Reveals Targets of a Pseudo-Natural-Product Autophagy Inhibitor2020In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 59, no 30Article in journal (Refereed)
    Abstract [en]

    Pseudo-natural-product (NP) design combines natural product fragments to provide unprecedented NP-inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo-NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell-based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd-catalyzed annulation. Exploration of indocinchona alkaloid bioactivities in phenotypic assays revealed a novel class of azaindole-containing autophagy inhibitors, the azaquindoles. Subsequent characterization of the most potent compound, azaquindole-1, in the morphological cell painting assay, guided target identification efforts. In contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation- and rapamycin-induced autophagy by targeting the lipid kinase VPS34.

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  • 8.
    Jia, Xiaotong
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Knyazeva, Anastasia
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Zhang, Yu
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Castro-Gonzalez, Sergio
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nakamura, Shuhei
    Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Yoshimori, Tamotsu
    Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
    Corkery, Dale
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    V. cholerae MakA is a cholesterol-binding pore-forming toxin that induces non-canonical autophagy2022In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 221, no 12, article id e202206040Article in journal (Refereed)
    Abstract [en]

    Pore-forming toxins (PFTs) are important virulence factors produced by many pathogenic bacteria. Here, we show that the Vibrio cholerae toxin MakA is a novel cholesterol-binding PFT that induces non-canonical autophagy in a pH-dependent manner. MakA specifically binds to cholesterol on the membrane at pH < 7. Cholesterol-binding leads to oligomerization of MakA on the membrane and pore formation at pH 5.5. Unlike other cholesterol-dependent cytolysins (CDCs) which bind cholesterol through a conserved cholesterol-binding motif (Thr-Leu pair), MakA contains an Ile-Ile pair that is essential for MakA-cholesterol interaction. Following internalization, endosomal acidification triggers MakA pore-assembly followed by ESCRT-mediated membrane repair and V-ATPase-dependent unconventional LC3 lipidation on the damaged endolysosomal membranes. These findings characterize a new cholesterol-binding toxin that forms pores in a pH-dependent manner and reveals the molecular mechanism of host autophagy manipulation.

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  • 9. Kaiser, Nadine
    et al.
    Corkery, Dale
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Laraia, Luca
    Waldmann, Herbert
    Modulation of autophagy by the novel mitochondrial complex I inhibitor Authipyrin2019In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 27, no 12, p. 2444-2448Article in journal (Refereed)
    Abstract [en]

    Autophagy ensures cellular homeostasis by the degradation of long-lived proteins, damaged organelles and pathogens. This catabolic process provides essential cellular building blocks upon nutrient deprivation. Cellular metabolism, especially mitochondrial respiration, has a significant influence on autophagic flux, and complex I function is required for maximal autophagy. In Parkinson’s disease mitochondrial function is frequently impaired and autophagic flux is altered. Thus, dysfunctional organelles and protein aggregates accumulate and cause cellular damage. In order to investigate the interdependency between mitochondrial function and autophagy, novel tool compounds are required. Herein, we report the discovery of a structurally novel autophagy inhibitor (Authipyrin) using a high content screening approach. Target identification and validation led to the discovery that Authipyrin targets mitochondrial complex I directly, leading to the potent inhibition of mitochondrial respiration as well as autophagy.

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  • 10.
    Knyazeva, Anastasia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Corkery, Dale
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Shankar, Kasturika
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Herzog, Laura K.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Zhang, Xuepei
    Chemical Proteomics Core Facility, Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Chemical Proteomics Unit, SciLifeLab, Stockholm, Sweden; Chemical Proteomics, Swedish National Infrastructure for Biological Mass Spectrometry (BioMS), Stockholm, Sweden.
    Singh, Birendra
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Niggemeyer, Georg
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
    Grill, David
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gaetani, Massimiliano
    Chemical Proteomics Core Facility, Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Chemical Proteomics Unit, SciLifeLab, Stockholm, Sweden; Chemical Proteomics, Swedish National Infrastructure for Biological Mass Spectrometry (BioMS), Stockholm, Sweden.
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Waldmann, Herbert
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany; Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany.
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Chemogenetic inhibition of IST1-CHMP1B interaction impairs endosomal recycling and promotes unconventional LC3 lipidation at stalled endosomesManuscript (preprint) (Other academic)
  • 11.
    Knyazeva, Anastasia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Science for Life Laboratory, Umeå University, Umeå, Sweden.
    Li, Shuang
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Science for Life Laboratory, Umeå University, Umeå, Sweden.
    Corkery, Dale P.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Science for Life Laboratory, Umeå University, Umeå, Sweden.
    Shankar, Kasturika
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Herzog, Laura K.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Zhang, Xuepei
    Chemical Proteomics Core Facility, Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Chemical Proteomics Unit, Science for Life Laboratory, Stockholm, Sweden; Chemical Proteomics, Swedish National Infrastructure for Biological Mass Spectrometry, Stockholm, Sweden.
    Singh, Birendra
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Niggemeyer, Georg
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
    Grill, David
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Gaetani, Massimiliano
    Chemical Proteomics Core Facility, Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Chemical Proteomics Unit, Science for Life Laboratory, Stockholm, Sweden; Chemical Proteomics, Swedish National Infrastructure for Biological Mass Spectrometry, Stockholm, Sweden.
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Waldmann, Herbert
    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany; Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany.
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Science for Life Laboratory, Umeå University, Umeå, Sweden.
    A chemical inhibitor of IST1-CHMP1B interaction impairs endosomal recycling and induces noncanonical LC3 lipidation2024In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 121, no 17, article id e2317680121Article in journal (Refereed)
    Abstract [en]

    The endosomal sorting complex required for transport (ESCRT) machinery constitutes multisubunit protein complexes that play an essential role in membrane remodeling and trafficking. ESCRTs regulate a wide array of cellular processes, including cytokinetic abscission, cargo sorting into multivesicular bodies (MVBs), membrane repair, and autophagy. Given the versatile functionality of ESCRTs, and the intricate organizational structure of the ESCRT machinery, the targeted modulation of distinct ESCRT complexes is considerably challenging. This study presents a pseudonatural product targeting IST1-CHMP1B within the ESCRT-III complexes. The compound specifically disrupts the interaction between IST1 and CHMP1B, thereby inhibiting the formation of IST1-CHMP1B copolymers essential for normal-topology membrane scission events. While the compound has no impact on cytokinesis, MVB sorting, or biogenesis of extracellular vesicles, it rapidly inhibits transferrin receptor recycling in cells, resulting in the accumulation of transferrin in stalled sorting endosomes. Stalled endosomes become decorated by lipidated LC3, suggesting a link between noncanonical LC3 lipidation and inhibition of the IST1-CHMP1B complex.

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  • 12. Laraia, Luca
    et al.
    Friese, Alexandra
    Corkery, Dale
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany.
    Konstantinidis, Georgios
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany.
    Erwin, Nelli
    Hofer, Walter
    Karatas, Hacer
    Klewer, Laura
    Brockmeyer, Andreas
    Metz, Malte
    Schoelermann, Beate
    Dwivedi, Mridula
    Li, Lei
    Rios-Munoz, Pablo
    Koehn, Maja
    Winter, Roland
    Vetter, Ingrid R.
    Ziegler, Slava
    Janning, Petra
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany.
    Waldmann, Herbert
    The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis2019In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 15, no 7, p. 710-720Article in journal (Refereed)
    Abstract [en]

    Autophagy mediates the degradation of damaged proteins, organelles and pathogens, and plays a key role in health and disease. Thus, the identification of new mechanisms involved in the regulation of autophagy is of major interest. In particular, little is known about the role of lipids and lipid-binding proteins in the early steps of autophagosome biogenesis. Using target-agnostic, high-content, image-based identification of indicative phenotypic changes induced by small molecules, we have identified autogramins as a new class of autophagy inhibitor. Autogramins selectively target the recently discovered cholesterol transfer protein GRAM domain-containing protein 1A (GRAMD1A, which had not previously been implicated in autophagy), and directly compete with cholesterol binding to the GRAMD1A StART domain. GRAMD1A accumulates at sites of autophagosome initiation, affects cholesterol distribution in response to starvation and is required for autophagosome biogenesis. These findings identify a new biological function of GRAMD1A and a new role for cholesterol in autophagy.

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  • 13. Laraia, Luca
    et al.
    Garivet, Guillaume
    Foley, Daniel J.
    Kaiser, Nadine
    Mueller, Sebastian
    Zinken, Sarah
    Pinkert, Thomas
    Wilke, Julian
    Corkery, Dale
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pahl, Axel
    Sievers, Sonja
    Janning, Petra
    Arenz, Christoph
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Rodriguez, Raphael
    Waldmann, Herbert
    Image-Based Morphological Profiling Identifies a Lysosomotropic, Iron-Sequestering Autophagy Inhibitor2020In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 59, p. 5721-5729Article in journal (Refereed)
    Abstract [en]

    Chemical proteomics is widely applied in small-molecule target identification. However, in general it does not identify non-protein small-molecule targets, and thus, alternative methods for target identification are in high demand. We report the discovery of the autophagy inhibitor autoquin and the identification of its molecular mode of action using image-based morphological profiling in the cell painting assay. A compound-induced fingerprint representing changes in 579 cellular parameters revealed that autoquin accumulates in lysosomes and inhibits their fusion with autophagosomes. In addition, autoquin sequesters Fe2+ in lysosomes, resulting in an increase of lysosomal reactive oxygen species and ultimately cell death. Such a mechanism of action would have been challenging to unravel by current methods. This work demonstrates the potential of the cell painting assay to deconvolute modes of action of small molecules, warranting wider application in chemical biology.

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  • 14.
    Niggemeyer, Georg
    et al.
    Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, Germany; Technical University Dortmund, Faculty of Chemistry, Chemical Biology, Otto-Hahn-Strasse 6, Dortmund, Germany.
    Knyazeva, Anastasia
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Gasper, Raphael
    Max Planck Institute of Molecular Physiology, Crystallography and Biophysics Unit, Otto-Hahn-Strasse 11, Dortmund, Germany.
    Corkery, Dale
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bodenbinder, Pia
    Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, Germany; Technical University Dortmund, Faculty of Chemistry, Chemical Biology, Otto-Hahn-Strasse 6, Dortmund, Germany.
    Holstein, Julian J.
    Technical University Dortmund, Faculty of Chemistry, Chemical Biology, Otto-Hahn-Strasse 6, Dortmund, Germany; Technical University Dortmund, Faculty of Chemistry, Inorganic Chemistry, Otto-Hahn-Strasse 6, Dortmund, Germany.
    Sievers, Sonja
    Compound Management and Screening Center (COMAS), Otto-Hahn-Strasse 11, Dortmund, Germany.
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Waldmann, Herbert
    Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, Dortmund, Germany; Technical University Dortmund, Faculty of Chemistry, Chemical Biology, Otto-Hahn-Strasse 6, Dortmund, Germany.
    Synthesis of 20-Membered Macrocyclic Pseudo-Natural Products Yields Inducers of LC3 Lipidation2022In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 61, no 11, article id e202114328Article in journal (Refereed)
    Abstract [en]

    Design and synthesis of pseudo-natural products (PNPs) through recombination of natural product (NP) fragments in unprecedented arrangements enables the discovery of novel biologically relevant chemical matter. With a view to wider coverage of NP-inspired chemical and biological space, we describe the combination of this principle with macrocycle formation. PNP-macrocycles were synthesized efficiently in a stereoselective one-pot procedure including the 1,3-dipolar cycloadditions of different dipolarophiles with dimeric cinchona alkaloid-derived azomethine ylides formed in situ. The 20-membered bis-cycloadducts embody 18 stereocenters and an additional fragment-sized NP-structure. After further functionalization, a collection of 163 macrocyclic PNPs was obtained. Biological investigation revealed potent inducers of the lipidation of the microtubule associated protein 1 light chain 3 (LC3) protein, which plays a prominent role in various autophagy-related processes.

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  • 15.
    Xin, Xiaoyi
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Zhang, Yu
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Gaetani, Massimiliano
    Division of Physiological Chemistry I, Chemical Proteomics Core Facility, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Chemical Proteomics, Science for Life Laboratory (SciLifeLab), Stockholm, Sweden.
    Lundström, Susanna L.
    Division of Physiological Chemistry I, Chemical Proteomics Core Facility, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17177, Sweden;Chemical Proteomics, Science for Life Laboratory (SciLifeLab), Stockholm, Sweden.
    Zubarev, Roman A.
    Division of Physiological Chemistry I, Chemical Proteomics Core Facility, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17177, Sweden;Chemical Proteomics, Science for Life Laboratory (SciLifeLab), Stockholm, Sweden.
    Zhou, Yuan
    School of Medical Technology, Xuzhou Medical University, Xuzhou, China.
    Corkery, Dale P.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wu, Yao-Wen
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Ultrafast and selective labeling of endogenous proteins using affinity-based benzotriazole chemistry2022In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 13, no 24, p. 7240-7246Article in journal (Refereed)
    Abstract [en]

    Chemical modification of proteins is enormously useful for characterizing protein function in complex biological systems and for drug development. Selective labeling of native or endogenous proteins is challenging owing to the existence of distinct functional groups in proteins and in living systems. Chemistry for rapid and selective labeling of proteins remains in high demand. Here we have developed novel affinity labeling probes using benzotriazole (BTA) chemistry. We showed that affinity-based BTA probes selectively and covalently label a lysine residue in the vicinity of the ligand binding site of a target protein with a reaction half-time of 28 s. The reaction rate constant is comparable to the fastest biorthogonal chemistry. This approach was used to selectively label different cytosolic and membrane proteins in vitro and in live cells. BTA chemistry could be widely useful for labeling of native/endogenous proteins, target identification and development of covalent inhibitors.

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