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Lundmark, Richard
Alternative names
Publications (10 of 48) Show all publications
Moren, B., Hansson, B., Negoita, F., Fryklund, C., Lundmark, R., Goransson, O. & Stenkula, K. G. (2019). EHD2 regulates adipocyte function and is enriched at cell surface-associated lipid droplets in primary human adipocytes. Molecular Biology of the Cell, 30(10), 1147-1159
Open this publication in new window or tab >>EHD2 regulates adipocyte function and is enriched at cell surface-associated lipid droplets in primary human adipocytes
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2019 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 30, no 10, p. 1147-1159Article in journal (Refereed) Published
Abstract [en]

Adipocytes play a central role in energy balance, and dysfunctional adipose tissue severely affects systemic energy homeostasis. The ATPase EH domain-containing 2 (EHD2) has previously been shown to regulate caveolae, plasma membrane-specific domains that are involved in lipid uptake and signal transduction. Here, we investigated the role of EHD2 in adipocyte function. We demonstrate that EHD2 protein expression is highly up-regulated at the onset of triglyceride accumulation during adipocyte differentiation. Small interfering RNA-mediated EHD2 silencing affected the differentiation process and impaired insulin sensitivity, lipid storage capacity, and lipolysis. Fluorescence imaging revealed localization of EHD2 to caveolae, close to cell surface-associated lipid droplets in primary human adipocytes. These lipid droplets stained positive for glycerol transporter aquaporin 7 and phosphorylated perilipin-1 following adrenergic stimulation. Further, EHD2 overexpression in human adipocytes increased the lipolytic signaling and suppressed the activity of transcription factor PPAR.. Overall, these data suggest that EHD2 plays a key role for adipocyte function.

Place, publisher, year, edition, pages
AMER SOC CELL BIOLOGY, 2019
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-158942 (URN)10.1091/mbc.E18-10-0680 (DOI)000466151300003 ()30811273 (PubMedID)
Available from: 2019-05-27 Created: 2019-05-27 Last updated: 2019-05-27Bibliographically approved
Moodie, L. W. K., Hubert, M., Zhou, X., Albers, M. F., Lundmark, R., Wanrooij, S. & Hedberg, C. (2019). Photoactivated Colibactin Probes Induce Cellular DNA Damage. Angewandte Chemie International Edition, 58(5), 1417-1421
Open this publication in new window or tab >>Photoactivated Colibactin Probes Induce Cellular DNA Damage
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2019 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 58, no 5, p. 1417-1421Article in journal (Refereed) Published
Abstract [en]

Colibactin is a small molecule produced by certain bacterial species of the human microbiota that harbour the pks genomic island. Pks(+) bacteria induce a genotoxic phenotype in eukaryotic cells and have been linked with colorectal cancer progression. Colibactin is produced in a benign, prodrug form which, prior to export, is enzymatically matured by the producing bacteria to its active form. Although the complete structure of colibactin has not been determined, key structural features have been described including an electrophilic cyclopropane motif, which is believed to alkylate DNA. To investigate the influence of the putative "warhead" and the prodrug strategy on genotoxicity, a series of photolabile colibactin probes were prepared that upon irradiation induced a pks(+) like phenotype in HeLa cells. Furthermore, results from DNA cross-linking and imaging studies of clickable analogues enforce the hypothesis that colibactin effects its genotoxicity by directly targeting DNA.

Keywords
click chemistry, colibactin, DNA damage, microbiome, photochemistry
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-156892 (URN)10.1002/anie.201812326 (DOI)000458826100026 ()30506956 (PubMedID)
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Nygård Skalman, L., Holst, M. R., Larsson, E. & Lundmark, R. (2018). Plasma membrane damage caused by listeriolysin O is not repaired through endocytosis of the membrane pore. Biology Open, 7(10)
Open this publication in new window or tab >>Plasma membrane damage caused by listeriolysin O is not repaired through endocytosis of the membrane pore
2018 (English)In: Biology Open, ISSN 2046-6390, Vol. 7, no 10Article in journal (Refereed) Published
Abstract [en]

Endocytic mechanisms have been suggested to be important for plasma membrane repair in response to pore-forming toxins such as listeriolysin O (LLO), which form membrane pores that disrupt cellular homeostasis. Yet, little is known about the specific role of distinct endocytic machineries in this process. Here, we have addressed the importance of key endocytic pathways and developed reporter systems for real-time imaging of the endocytic response to LLO pore formation. We found that loss of clathrin-independent endocytic pathways negatively influenced the efficiency of membrane repair. However, we did not detect any increased activity of these pathways, or co-localisation with the toxin or markers of membrane repair, suggesting that they were not directly involved in removal of LLO pores from the plasma membrane. In fact, markers of clathrin-independent carriers (CLICs) were rapidly disassembled in the acute phase of membrane damage due to Ca2+ influx, followed by a reassembly about 2 min after pore formation. We propose that these endocytic mechanisms might influence membrane repair by regulating the plasma membrane composition and tension, but not via direct internalisation of LLO pores.

Place, publisher, year, edition, pages
The Company of Biologists, 2018
Keywords
Membrane pore, Repair, Membrane damage, LLO, Listeriolysin, Caveolae, Clathrin-mediated endocytosis, Clathrin-independent endocytosis, CLIC
National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-153708 (URN)10.1242/bio.035287 (DOI)000448607800009 ()30254077 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research The Kempe Foundations
Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2018-12-05Bibliographically approved
Kong, Z., Jia, S., Chabes, A. L., Appelblad, P., Lundmark, R., Moritz, T. & Chabes, A. (2018). Simultaneous determination of ribonucleoside and deoxyribonucleoside triphosphates in biological samples by hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry. Nucleic Acids Research, 46(11), Article ID e66.
Open this publication in new window or tab >>Simultaneous determination of ribonucleoside and deoxyribonucleoside triphosphates in biological samples by hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry
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2018 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 11, article id e66Article in journal (Refereed) Published
Abstract [en]

Information about the intracellular concentration of dNTPs and NTPs is important for studies of the mechanisms of DNA replication and repair, but the low concentration of dNTPs and their chemical similarity to NTPs present a challenge for their measurement. Here, we describe a new rapid and sensitive method utilizing hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry for the simultaneous determination of dNTPs and NTPs in biological samples. The developed method showed linearity (R2 > 0.99) in wide concentration ranges and could accurately quantify dNTPs and NTPs at low pmol levels. The intra-day and inter-day precision were below 13%, and the relative recovery was between 92% and 108%. In comparison with other chromatographic methods, the current method has shorter analysis times and simpler sample pre-treatment steps, and it utilizes an ion-pair-free mobile phase that enhances mass-spectrometric detection. Using this method, we determined dNTP and NTP concentrations in actively dividing and quiescent mouse fibroblasts.

Place, publisher, year, edition, pages
Oxford University Press, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-145936 (URN)10.1093/nar/gky203 (DOI)000438362400003 ()29554314 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-09-28Bibliographically approved
Vonderstein, K., Nilsson, E., Hubel, P., Nygård Skalman, L., Upadhyay, A., Pasto, J., . . . Överby, A. K. (2018). Viperin targets flavivirus virulence by inducing assembly of non-infectious capsid particles. Journal of Virology, 92(1), Article ID e01751-17.
Open this publication in new window or tab >>Viperin targets flavivirus virulence by inducing assembly of non-infectious capsid particles
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2018 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, no 1, article id e01751-17Article in journal (Refereed) Published
Abstract [en]

Efficient antiviral immunity requires interference with virus replication at multiple layers targeting diverse steps in the viral life cycle. Here we describe a novel flavivirus inhibition mechanism that results in interferon-mediated obstruction of tick-borne encephalitis virus particle assembly, and involves release of malfunctional membrane associated capsid (C) particles. This mechanism is controlled by the activity of the interferon-induced protein viperin, a broad spectrum antiviral interferon stimulated gene. Through analysis of the viperin-interactome, we identified the Golgi Brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1), as the cellular protein targeted by viperin. Viperin-induced antiviral activity as well as C-particle release was stimulated by GBF1 inhibition and knock down, and reduced by elevated levels of GBF1. Our results suggest that viperin targets flavivirus virulence by inducing the secretion of unproductive non-infectious virus particles, by a GBF1-dependent mechanism. This yet undescribed antiviral mechanism allows potential therapeutic intervention.Importance The interferon response can target viral infection on almost every level, however, very little is known about interference of flavivirus assembly. Here we show that interferon, through the action of viperin, can disturb assembly of tick-borne encephalitis virus. The viperin protein is highly induced after viral infection and exhibit broad-spectrum antiviral activity. However, the mechanism of action is still elusive and appear to vary between the different viruses, indicating that cellular targets utilized by several viruses might be involved. In this study we show that viperin induce capsid particle release by interacting and inhibiting the function of the cellular protein Golgi Brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1). GBF1 is a key protein in the cellular secretory pathway and essential in the life cycle of many viruses, also targeted by viperin, implicating GBF1 as a novel putative drug target.

Place, publisher, year, edition, pages
American Society of Microbiology, 2018
Keywords
COPI,  COPII,  GBF1,  assembly,  capsid,  flavivirus,  interferon,  tick-borne encephalitis virus,  viperi
National Category
Microbiology in the medical area Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-143054 (URN)10.1128/JVI.01751-17 (DOI)000417922700037 ()29046456 (PubMedID)
Funder
Swedish Research Council, 2011-2795Swedish Foundation for Strategic Research , ICA10-0059, FFL12-0089, FFL09-0181
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2018-06-09Bibliographically approved
Vdovikova, S., Luhr, M., Szalai, P., Skalman, L. N., Francis, M. K., Lundmark, R., . . . Wai, S. N. (2017). A Novel Role of Listeria monocytogenes Membrane Vesicles in Inhibition of Autophagy and Cell Death. Frontiers in Cellular and Infection Microbiology, 7, Article ID 154.
Open this publication in new window or tab >>A Novel Role of Listeria monocytogenes Membrane Vesicles in Inhibition of Autophagy and Cell Death
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2017 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 7, article id 154Article in journal (Refereed) Published
Abstract [en]

Bacterial membrane vesicle (MV) production has been mainly studied in Gram-negative species. In this study, we show that Listeria monocytogenes, a Gram-positive pathogen that causes the food-borne illness listeriosis, produces MVs both in vitro and in vivo. We found that a major virulence factor, the pore-forming hemolysin listeriolysin O (LLO), is tightly associated with the MVs, where it resides in an oxidized, inactive state. Previous studies have shown that LLO may induce cell death and autophagy. To monitor possible effects of LLO and MVs on autophagy, we performed assays for LC3 lipidation and LDH sequestration as well as analysis by confocal microscopy of HEK293 cells expressing GFP-LC3. The results revealed that MVs alone did not affect autophagy whereas they effectively abrogated autophagy induced by pure LLO or by another pore-forming toxin from Vibrio cholerae, VCC. Moreover, Listeria monocytogenes MVs significantly decreased Torin1-stimulated macroautophagy. In addition, MVs protected against necrosis of HEK293 cells caused by the lytic action of LLO. We explored the mechanisms of LLO-induced autophagy and cell death and demonstrated that the protective effect of MVs involves an inhibition of LLO-induced pore formation resulting in inhibition of autophagy and the lytic action on eukaryotic cells. Further, we determined that these MVs help bacteria to survive inside eukaryotic cells (mouse embryonic fibroblasts). Taken together, these findings suggest that intracellular release of MVs from L. monocytogenes may represent a bacterial strategy to survive inside host cells, by its control of LLO activity and by avoidance of destruction from the autophagy system during infection.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2017
Keywords
Listeria monocytogenes, membrane vesicles, autophagy, listeriolysin O, pore-forming toxin
National Category
Immunology in the medical area Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-136187 (URN)10.3389/fcimb.2017.00154 (DOI)000400405800001 ()28516064 (PubMedID)
Available from: 2017-07-07 Created: 2017-07-07 Last updated: 2018-06-09Bibliographically approved
Hubert, M., Larsson, E. & Lundmark, R. (2017). Caveolae dynamics is strongly influenced by the lipid composition of the plasma membrane. Paper presented at 19th IUPAB Congress / 11th EBSA Congress, JUL 16-20, 2017, British Biophys Soc, Edinburgh, SCOTLAND. European Biophysics Journal, 46, S121-S121
Open this publication in new window or tab >>Caveolae dynamics is strongly influenced by the lipid composition of the plasma membrane
2017 (English)In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 46, p. S121-S121Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2017
National Category
Biophysics
Identifiers
urn:nbn:se:umu:diva-143671 (URN)000416406200233 ()
Conference
19th IUPAB Congress / 11th EBSA Congress, JUL 16-20, 2017, British Biophys Soc, Edinburgh, SCOTLAND
Available from: 2018-01-16 Created: 2018-01-16 Last updated: 2018-06-09Bibliographically approved
Kindstedt, E., Koskinen Holm, C., Sulniute, R., Martinez-Carrasco, I., Lundmark, R. & Lundberg, P. (2017). CCL11, a novel mediator of inflammatory bone resorption. Scientific Reports, 7(1), Article ID 5334.
Open this publication in new window or tab >>CCL11, a novel mediator of inflammatory bone resorption
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 5334Article in journal (Refereed) Published
Abstract [en]

Normal bone homeostasis, which is regulated by bone-resorbing osteoclasts and bone-forming osteoblasts is perturbed by inflammation. Inchronic inflammatory disease with disturbed bone remodelling, e.g. rheumatoid arthritis, patients show increased serum levels of the chemokine eotaxin-1 (CCL11). Herein, we demonstrate an inflammatory driven expression of CCL11 in bone tissue and a novel role of CCL11 in osteoclast migration and resorption. Using an inflammatory bone lesion model and primary cell cultures, we discovered that osteoblasts express CCL11 in vivo and in vitro and that expression increased during inflammatory conditions. Osteoclasts did not express CCL11, but the high affinity receptor CCR3 was significantly upregulated during osteoclast differentiation and found to colocalise with CCL11. Exogenous CCL11 was internalised in osteoclast and stimulated the migration of pre-osteoclast and concomitant increase in bone resorption. Our data pinpoints that the CCL11/CCR3 pathway could be a new target for treatment of inflammatory bone resorption.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
National Category
Rheumatology and Autoimmunity
Research subject
biology
Identifiers
urn:nbn:se:umu:diva-139690 (URN)10.1038/s41598-017-05654-w (DOI)000425912800001 ()28706221 (PubMedID)
Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2018-06-09Bibliographically approved
Holst, M. R., Vidal-Quadras, M., Larsson, E., Song, J., Hubert, M., Blomberg, J., . . . Lundmark, R. (2017). Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion. Cell reports, 20(8), 1893-1905
Open this publication in new window or tab >>Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion
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2017 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, no 8, p. 1893-1905Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Cell Press, 2017
Keywords
Endocytosis, clathrin-independent endocytosis, membrane blebbing, membrane tension, GRAF1, cancer invasion, cell migration, ARHGAP26, cell surface dynamics, GRAF1-dependent endocytosis
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-139144 (URN)10.1016/j.celrep.2017.08.006 (DOI)000408154300014 ()28834752 (PubMedID)
Available from: 2017-09-15 Created: 2017-09-15 Last updated: 2019-05-10Bibliographically approved
Daste, F., Walrant, A., Holst, M. R., Gadsby, J. R., Mason, J., Lee, J.-E., . . . Gallop, J. L. (2017). Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature. Journal of Cell Biology, 216(11), 3745-3765
Open this publication in new window or tab >>Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature
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2017 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 216, no 11, p. 3745-3765Article in journal (Refereed) Published
Abstract [en]

The conditional use of actin during clathrin-mediated endocytosis in mammalian cells suggests that the cell controls whether and how actin is used. Using a combination of biochemical reconstitution and mammalian cell culture, we elucidate a mechanism by which the coincidence of PI(4,5)P-2 and PI(3)P in a curved vesicle triggers actin polymerization. At clathrin-coated pits, PI(3) P is produced by the INPP4A hydrolysis of PI(3,4)P-2, and this is necessary for actin-driven endocytosis. Both Cdc42.guanosine triphosphate and SNX9 activate N-WASP-WIP-and Arp2/3-mediated actin nucleation. Membrane curvature, PI(4,5)P-2, and PI(3) P signals are needed for SNX9 assembly via its PX-BAR domain, whereas signaling through Cdc42 is activated by PI(4,5)P-2 alone. INPP4A activity is stimulated by high membrane curvature and synergizes with SNX9 BAR domain binding in a process we call curvature cascade amplification. We show that the SNX9-driven actin comets that arise on human disease-associated oculocerebrorenal syndrome of Lowe (OCRL) deficiencies are reduced by inhibiting PI(3) P production, suggesting PI(3) P kinase inhibitors as a therapeutic strategy in Lowe syndrome.

Place, publisher, year, edition, pages
ROCKEFELLER UNIV PRESS, 2017
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-142260 (URN)10.1083/jcb.201704061 (DOI)000414609700026 ()
Funder
EU, Horizon 2020, 281971
Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2018-06-09Bibliographically approved
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