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Carlsson, Sven R
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Publications (10 of 26) Show all publications
Lystad, A. H., Carlsson, S. R., de la Ballina, L. R., Kauffman, K. J., Nag, S., Yoshimori, T., . . . Simonsen, A. (2019). Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processes. Nature Cell Biology, 21(3), 372-383
Open this publication in new window or tab >>Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processes
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2019 (English)In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 21, no 3, p. 372-383Article in journal (Refereed) Published
Abstract [en]

Covalent modification of LC3 and GABARAP proteins to phosphatidylethanolamine in the double-membrane phagophore is a key event in the early phase of macroautophagy, but can also occur on single-membrane structures. In both cases this involves transfer of LC3/GABARAP from ATG3 to phosphatidylethanolamine at the target membrane. Here we have purified the full-length human ATG12-5-ATG16L1 complex and show its essential role in LC3B/GABARAP lipidation in vitro. We have identified two functionally distinct membrane-binding regions in ATG16L1. An N-terminal membrane-binding amphipathic helix is required for LC3B lipidation under all conditions tested. By contrast, the C-terminal membrane-binding region is dispensable for canonical autophagy but essential for VPS34-independent LC3B lipidation at perturbed endosomes. We further show that the ATG16L1 C-terminus can compensate for WIPI2 depletion to sustain lipidation during starvation. This C-terminal membrane-binding region is present only in the beta-isoform of ATG16L1, showing that ATG16L1 isoforms mechanistically distinguish between different LC3B lipidation mechanisms under different cellular conditions.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Biophysics
Identifiers
urn:nbn:se:umu:diva-157525 (URN)10.1038/s41556-019-0274-9 (DOI)000460120500012 ()30778222 (PubMedID)
Available from: 2019-04-03 Created: 2019-04-03 Last updated: 2019-04-03Bibliographically approved
Lystad, A. H., Carlsson, S. R. & Simonsen, A. (2019). Toward the function of mammalian ATG12-ATG5-ATG16L1 complex in autophagy and related processes. Autophagy, 15(8), 1485-1486
Open this publication in new window or tab >>Toward the function of mammalian ATG12-ATG5-ATG16L1 complex in autophagy and related processes
2019 (English)In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 15, no 8, p. 1485-1486Article in journal (Refereed) Published
Abstract [en]

The machinery that decorates autophagic membranes with lipid-conjugated LC3/GABARAP is not yet fully understood. We recently reported the purification of the full-length ATG12-ATG5-ATG16L1 complex, and in reconstitution experiments with purified ATG7, ATG3, and LC3/GABARAP in vitro, together with rescue experiments in knockout cells, important aspects of the complete lipidation reaction were revealed. Hitherto unobserved membrane-binding regions in ATG16L1 were found, contributing to properties that explain the crucial role of this protein in membrane targeting and LC3/GABARAP lipidation in macroautophagy/autophagy and other related processes.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2019
Keywords
Amphipathic helix, autophagy, endosome, GABARAP, LAP, LC3, lipidation, membrane
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-160610 (URN)10.1080/15548627.2019.1618100 (DOI)000470532900001 ()31122169 (PubMedID)
Available from: 2019-06-24 Created: 2019-06-24 Last updated: 2020-01-07Bibliographically approved
Søreng, K., Munson, M. J., Lamb, C. A., Bjørndal, G. T., Pankiv, S., Carlsson, S. R., . . . Simonsen, A. (2018). SNX18 regulates ATG9A trafficking from recycling endosomes by recruiting Dynamin-2. EMBO Reports, 19(4), Article ID e44837.
Open this publication in new window or tab >>SNX18 regulates ATG9A trafficking from recycling endosomes by recruiting Dynamin-2
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2018 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 19, no 4, article id e44837Article in journal (Refereed) Published
Abstract [en]

Trafficking of mammalian ATG9A between the Golgi apparatus, endosomes and peripheral ATG9A compartments is important for autophagosome biogenesis. Here, we show that the membrane remodelling protein SNX18, previously identified as a positive regulator of autophagy, regulates ATG9A trafficking from recycling endosomes. ATG9A is recruited to SNX18-induced tubules generated from recycling endosomes and accumulates in juxtanuclear recycling endosomes in cells lacking SNX18. Binding of SNX18 to Dynamin-2 is important for ATG9A trafficking from recycling endosomes and for formation of ATG16L1- and WIPI2-positive autophagosome precursor membranes. We propose a model where upon autophagy induction, SNX18 recruits Dynamin-2 to induce budding of ATG9A and ATG16L1 containing membranes from recycling endosomes that traffic to sites of autophagosome formation.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
ATG9, autophagy, dynamin, recycling endosome, SNX18
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-147339 (URN)10.15252/embr.201744837 (DOI)000429540900006 ()29437695 (PubMedID)
Available from: 2018-05-11 Created: 2018-05-11 Last updated: 2018-06-09Bibliographically approved
Klionsky, D. J., Carlsson, S. R. & Zughaier, S. M. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy, 12(1), 1-222
Open this publication in new window or tab >>Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
2016 (English)In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 12, no 1, p. 1-222Article in journal (Refereed) Published
Keywords
autolysosome, autophagosome‚ chaperone-mediated autophagy, flux, LC3, lysosome, macroautophagy, phagophore, stress, vacuole
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-130139 (URN)10.1080/15548627.2015.1100356 (DOI)000373595400001 ()26799652 (PubMedID)
Available from: 2017-01-12 Created: 2017-01-12 Last updated: 2018-06-09Bibliographically approved
Holland, P., Knaevelsrud, H., Soreng, K., Mathai, B. J., Lystad, A. H., Pankiv, S., . . . Simonsen, A. (2016). HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels. Nature Communications, 7, Article ID 13889.
Open this publication in new window or tab >>HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels
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2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 13889Article in journal (Refereed) Published
Abstract [en]

A fundamental question is how autophagosome formation is regulated. Here we show that the PX domain protein HS1BP3 is a negative regulator of autophagosome formation. HS1BP3 depletion increased the formation of LC3-positive autophagosomes and degradation of cargo both in human cell culture and in zebrafish. HS1BP3 is localized to ATG16L1-and ATG9-positive autophagosome precursors and we show that HS1BP3 binds phosphatidic acid (PA) through its PX domain. Furthermore, we find the total PA content of cells to be significantly upregulated in the absence of HS1BP3, as a result of increased activity of the PA-producing enzyme phospholipase D (PLD) and increased localization of PLD1 to ATG16L1-positive membranes. We propose that HS1BP3 regulates autophagy by modulating the PA content of the ATG16L1-positive autophagosome precursor membranes through PLD1 activity and localization. Our findings provide key insights into how autophagosome formation is regulated by a novel negative-feedback mechanism on membrane lipids.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-130221 (URN)10.1038/ncomms13889 (DOI)000390284700001 ()
Available from: 2017-01-17 Created: 2017-01-14 Last updated: 2018-06-09Bibliographically approved
Carlsson, S. R. & Simonsen, A. (2015). Membrane dynamics in autophagosome biogenesis. Journal of Cell Science, 128(2), 193-205
Open this publication in new window or tab >>Membrane dynamics in autophagosome biogenesis
2015 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 128, no 2, p. 193-205Article in journal, Editorial material (Other academic) Published
Abstract [en]

Bilayered phospholipid membranes are vital to the organization of the living cell. Based on fundamental principles of polarity, membranes create borders allowing defined spaces to be encapsulated. This compartmentalization is a prerequisite for the complex functional design of the eukaryotic cell, yielding localities that can differ in composition and operation. During macroautophagy, cytoplasmic components become enclosed by a growing double bilayered membrane, which upon closure creates a separate compartment, the autophagosome. The autophagosome is then primed for fusion with endosomal and lysosomal compartments, leading to degradation of the captured material. A large number of proteins have been found to be essential for autophagy, but little is known about the specific lipids that constitute the autophagic membranes and the membrane modeling events that are responsible for regulation of autophagosome shape and size. In this Commentary, we review the recent progress in our understanding of the membrane shaping and remodeling events that are required at different steps of the autophagy pathway.

Place, publisher, year, edition, pages
The Company of Biologists LTD, 2015
Keywords
Atg, PtdIns3P, Autophagosome, Phagophore
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-100292 (URN)10.1242/jcs.141036 (DOI)000347973900002 ()
Available from: 2015-03-04 Created: 2015-02-27 Last updated: 2018-06-07Bibliographically approved
Carlsson, S. R. & Simonsen, A. (2015). Recycling endosomes and autophagy. Cell Technology (Saibou Kougaku), 34(2), 138-142
Open this publication in new window or tab >>Recycling endosomes and autophagy
2015 (Japanese)In: Cell Technology (Saibou Kougaku), Vol. 34, no 2, p. 138-142Article in journal (Other academic) Published
Place, publisher, year, edition, pages
Tokyo: Gakken Medical Shujunsha Co., 2015
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-108539 (URN)
Available from: 2015-09-14 Created: 2015-09-14 Last updated: 2018-06-07Bibliographically approved
Elluri, S., Enow Oben Ayuk, C., Vdovikova, S., Rompikuntal, P. K., Dongre, M., Carlsson, S., . . . Wai, S. N. (2014). Outer membrane vesicles mediate transport of biologically active Vibrio cholerae cytolysin (VCC) from V. cholerae strains. PLoS ONE, 9(9), Article ID e106731.
Open this publication in new window or tab >>Outer membrane vesicles mediate transport of biologically active Vibrio cholerae cytolysin (VCC) from V. cholerae strains
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e106731Article in journal (Refereed) Published
Abstract [en]

Background Outer membrane vesicles (OMVs) released from Gram-negative bacteria can serve as vehicles for the translocation of virulence factors. Vibrio cholerae produce OMVs but their putative role in translocation of effectors involved in pathogenesis has not been well elucidated. The V. cholerae cytolysin (VCC), is a pore-forming toxin that lyses target eukaryotic cells by forming transmembrane oligomeric β-barrel channels. It is considered a potent toxin that contributes to V. cholerae pathogenesis. The mechanisms involved in the secretion and delivery of the VCC have not been extensively studied.

Methodology/Principal Findings OMVs from V. cholerae strains were isolated and purified using a differential centrifugation procedure and Optiprep centrifugation. The ultrastructure and the contents of OMVs were examined under the electron microscope and by immunoblot analyses respectively. We demonstrated that VCC from V. cholerae strain V:5/04 was secreted in association with OMVs and the release of VCC via OMVs is a common feature among V. cholerae strains. The biological activity of OMV-associated VCC was investigated using contact hemolytic assay and epithelial cell cytotoxicity test. It showed toxic activity on both red blood cells and epithelial cells. Our results indicate that the OMVs architecture might play a role in stability of VCC and thereby can enhance its biological activities in comparison with the free secreted VCC. Furthermore, we tested the role of OMV-associated VCC in host cell autophagy signalling using confocal microscopy and immunoblot analysis. We observed that OMV-associated VCC triggered an autophagy response in the target cell and our findings demonstrated for the first time that autophagy may operate as a cellular defence mechanism against an OMV-associated bacterial virulence factor.

Conclusion/Significance Biological assays of OMVs from the V. cholerae strain V:5/04 demonstrated that OMV-associated VCC is indeed biologically active and induces toxicity on mammalian cells and furthermore can induce autophagy.

Place, publisher, year, edition, pages
Public library of science, 2014
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-93659 (URN)10.1371/journal.pone.0106731 (DOI)000341271500078 ()25187967 (PubMedID)
Funder
Swedish Research Council, 2006-4702Swedish Research Council, 2013-2392Swedish Research Council, 353-2010-7074Swedish Research Council, 2010-3031Swedish Research Council, 2012-4638Swedish Research Council, 349-2007-8673The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2008-2049
Available from: 2014-09-29 Created: 2014-09-29 Last updated: 2018-10-10Bibliographically approved
Knævelsrud, H., Søreng, K., Raiborg, C., Håberg, K., Rasmuson, F., Brech, A., . . . Simonsen, A. (2013). Membrane remodeling by the PX-BAR protein SNX18 promotes autophagosome formation. Journal of Cell Biology, 202(2), 331-349
Open this publication in new window or tab >>Membrane remodeling by the PX-BAR protein SNX18 promotes autophagosome formation
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2013 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 202, no 2, p. 331-349Article in journal (Refereed) Published
Abstract [en]

The membrane remodeling events required for autophagosome biogenesis are still poorly understood. Because PX domain proteins mediate membrane remodeling and trafficking, we conducted an imaging-based siRNA screen for autophagosome formation targeting human PX proteins. The PX-BAR protein SNX18 was identified as a positive regulator of autophagosome formation, and its Drosophila melanogaster homologue SH3PX1 was found to be required for efficient autophagosome formation in the larval fat body. We show that SNX18 is required for recruitment of Atg16L1-positive recycling endosomes to a perinuclear area and for delivery of Atg16L1- and LC3-positive membranes to autophagosome precursors. We identify a direct interaction of SNX18 with LC3 and show that the pro-autophagic activity of SNX18 depends on its membrane binding and tubulation capacity. We also show that the function of SNX18 in membrane tubulation and autophagy is negatively regulated by phosphorylation of S233. We conclude that SNX18 promotes autophagosome formation by virtue of its ability to remodel membranes and provide membrane to forming autophagosomes.

Place, publisher, year, edition, pages
Rockefeller University Press, 2013
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-82409 (URN)10.1083/jcb.201205129 (DOI)000322062300015 ()23878278 (PubMedID)
Available from: 2013-10-31 Created: 2013-10-31 Last updated: 2018-06-08Bibliographically approved
Knævelsrud, H., Carlsson, S. R. & Simonsen, A. (2013). SNX18 tubulates recycling endosomes for autophagosome biogenesis. Autophagy, 9(10), 1639-1641
Open this publication in new window or tab >>SNX18 tubulates recycling endosomes for autophagosome biogenesis
2013 (English)In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, ISSN 1554-8635 (online), Vol. 9, no 10, p. 1639-1641Article in journal (Refereed) Published
Abstract [en]

The role of membrane remodeling and phosphoinositide-binding proteins in autophagy remains elusive. PX domain proteins bind phosphoinositides and participate in membrane remodeling and trafficking events and we therefore hypothesized that one or several PX domain proteins are involved in autophagy. Indeed, the PX-BAR protein SNX18 was identified as a positive regulator of autophagosome formation using an image-based siRNA screen. We show that SNX18 interacts with ATG16L1 and LC3, and functions downstream of ATG14 and the class III PtdIns3K complex in autophagosome formation. SNX18 facilitates recruitment of ATG16L1 to perinuclear recycling endosomes, and its overexpression leads to tubulation of ATG16L1- and LC3-positive membranes. We propose that SNX18 promotes LC3 lipidation and tubulation of recycling endosomes to provide membrane for phagophore expansion.

Place, publisher, year, edition, pages
Landes Bioscience, 2013
Keywords
SNX18, recycling endosomes, PX-BAR protein, autophagosome formation, ATG16L1, RAB11
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-82408 (URN)10.4161/auto.26124 (DOI)24113029 (PubMedID)
Available from: 2013-10-31 Created: 2013-10-31 Last updated: 2018-06-08Bibliographically approved
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