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Larsson, Elin
Publications (10 of 18) Show all publications
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
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
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
Hoernke, M., Mohan, J., Larsson, E., Kahra, D., Westenhoff, S., Lundmark, R. & Schwieger, C. (2017). Determining membrane bound protein structures by infrared reflection-absorption spectroscopy. Paper presented at 19th IUPAB Congress / 11th EBSA Congress, JUL 16-20, 2017, British Biophys Soc, Edinburgh, SCOTLAND. European Biophysics Journal, 46, S161-S161
Open this publication in new window or tab >>Determining membrane bound protein structures by infrared reflection-absorption spectroscopy
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2017 (English)In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 46, p. S161-S161Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2017
National Category
Biophysics
Identifiers
urn:nbn:se:umu:diva-143670 (URN)000416406201062 ()
Conference
19th IUPAB Congress / 11th EBSA Congress, JUL 16-20, 2017, British Biophys Soc, Edinburgh, SCOTLAND
Note

Supplement: 1, Meeting Abstract: P-177

Available from: 2018-01-16 Created: 2018-01-16 Last updated: 2018-06-09Bibliographically approved
Hoernke, M., Mohan, J., Larsson, E., Blomberg, J., Kahra, D., Westenhoff, S., . . . Lundmark, R. (2017). EHD2 restrains dynamics of caveolae by an ATP-dependent, membrane-bound, open conformation. Proceedings of the National Academy of Sciences of the United States of America, 114(22), E4360-E4369
Open this publication in new window or tab >>EHD2 restrains dynamics of caveolae by an ATP-dependent, membrane-bound, open conformation
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2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 22, p. E4360-E4369Article in journal (Refereed) Published
Abstract [en]

The EH-domain-containing protein 2 (EHD2) is a dynamin-related ATPase that confines caveolae to the cell surface by restricting the scission and subsequent endocytosis of these membrane pits. For this, EHD2 is thought to first bind to the membrane, then to oligomerize, and finally to detach, in a stringently regulated mechanistic cycle. It is still unclear how ATP is used in this process and whether membrane binding is coupled to conformational changes in the protein. Here, we show that the regulatory N-terminal residues and the EH domain keep the EHD2 dimer in an autoinhibited conformation in solution. By significantly advancing the use of infrared reflection-absorption spectroscopy, we demonstrate that EHD2 adopts an open conformation by tilting the helical domains upon membrane binding. We show that ATP binding enables partial insertion of EHD2 into the membrane, where G-domain-mediated oligomerization occurs. ATP hydrolysis is related to detachment of EHD2 from the membrane. Finally, we demonstrate that the regulation of EHD2 oligomerization in a membrane-bound state is crucial to restrict caveolae dynamics in cells.

Keywords
EHD2, caveolae, membrane-reshaping protein, membrane-bound protein structure, infrared flection-absorption spectroscopy
National Category
Biophysics
Identifiers
urn:nbn:se:umu:diva-136326 (URN)10.1073/pnas.1614066114 (DOI)000402296700009 ()28223496 (PubMedID)
Available from: 2017-06-22 Created: 2017-06-22 Last updated: 2018-06-09Bibliographically approved
Vidal-Quadras, M., Holst, M. R., Francis, M. K., Larsson, E., Hachimi, M., Yau, W.-L., . . . Lundmark, R. (2017). Endocytic turnover of Rab8 controls cell polarization. Journal of Cell Science, 130(6), 1147-1157
Open this publication in new window or tab >>Endocytic turnover of Rab8 controls cell polarization
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2017 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 130, no 6, p. 1147-1157Article in journal (Refereed) Published
Abstract [en]

Adaptation of cell shape and polarization through the formation and retraction of cellular protrusions requires balancing of endocytosis and exocytosis combined with fine-tuning of the local activity of small GTPases like Rab8. Here, we show that endocytic turnover of the plasma membrane at protrusions is directly coupled to surface removal and inactivation of Rab8. Removal is induced by reduced membrane tension and mediated by the GTPase regulator associated with focal adhesion kinase-1 (GRAF1, also known as ARHGAP26), a regulator of clathrin-independent endocytosis. GRAF1-depleted cells were deficient in multi-directional spreading and displayed elevated levels of GTP-loaded Rab8, which was accumulated at the tips of static protrusions. Furthermore, GRAF1 depletion impaired lumen formation and spindle orientation in a 3D cell culture system, indicating that GRAF1 activity regulates polarity establishment. Our data suggest that GRAF1-mediated removal of Rab8 from the cell surface restricts its activity during protrusion formation, thereby facilitating dynamic adjustment of the polarity axis.

Keywords
Rab8, GRAF1, Cell polarization, Endocytosis
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-133762 (URN)10.1242/jcs.195420 (DOI)000397907900012 ()28137756 (PubMedID)
Funder
Swedish Research Council, 811-2014-59Swedish Foundation for Strategic Research , FFL09-0181The Kempe Foundations, SMK1348
Available from: 2017-05-03 Created: 2017-05-03 Last updated: 2018-06-09Bibliographically approved
Melo, A. A., Hegde, B. G., Shah, C., Larsson, E., Isas, J. M., Kunz, S., . . . Daumke, O. (2017). Structural insights into the activation mechanism of dynamin-like EHD ATPases. Proceedings of the National Academy of Sciences of the United States of America, 114(22), 5629-5634
Open this publication in new window or tab >>Structural insights into the activation mechanism of dynamin-like EHD ATPases
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2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 22, p. 5629-5634Article in journal (Refereed) Published
Abstract [en]

Eps15 (epidermal growth factor receptor pathway substrate 15)homology domain containing proteins (EHDs) comprise a family of dynamin-related mechano-chemical ATPases involved in cellular membrane trafficking. Previous studies have revealed the structure of the EHD2 dimer, but the molecular mechanisms of membrane recruitment and assembly have remained obscure. Here, we determined the crystal structure of an amino-terminally truncated EHD4 dimer. Compared with the EHD2 structure, the helical domains are 50 degrees rotated relative to the GTPase domain. Using electron paramagnetic spin resonance (EPR), we show that this rotation aligns the two membrane-binding regions in the helical domain toward the lipid bilayer, allowing membrane interaction. A loop rearrangement in GTPase domain creates a new interface for oligomer formation. Our results suggest that the EHD4 structure represents the active EHD conformation, whereas the EHD2 structure is autoinhibited, and reveal a complex series of domain rearrangements accompanying activation. A comparison with other peripheral membrane proteins elucidates common and specific features of this activation mechanism.

Keywords
dynamin superfamily, endocytic pathways, protein structure, membrane remodeling, autoinhibition
National Category
Structural Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-136325 (URN)10.1073/pnas.1614075114 (DOI)000402296700043 ()28228524 (PubMedID)
Available from: 2017-06-26 Created: 2017-06-26 Last updated: 2018-06-09Bibliographically approved
Hoernke, M., Larsson, E., Mohan, J., Blomberg, J., Westenhoff, S., Lundmark, R. & Schwieger, C. (2016). Structural Mechanism in a Membrane Remodelling ATP-ASE. Paper presented at 60th Annual Meeting of the Biophysical-Society, FEB 27-MAR 02, 2016, Los Angeles, CA. Biophysical Journal, 110(3), 578A-578A
Open this publication in new window or tab >>Structural Mechanism in a Membrane Remodelling ATP-ASE
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2016 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 3, p. 578A-578AArticle in journal, Meeting abstract (Other academic) Published
National Category
Biophysics
Identifiers
urn:nbn:se:umu:diva-121607 (URN)000375143000319 ()
Conference
60th Annual Meeting of the Biophysical-Society, FEB 27-MAR 02, 2016, Los Angeles, CA
Available from: 2016-06-21 Created: 2016-06-03 Last updated: 2018-06-07Bibliographically approved
Mohan, J., Morén, B., Larsson, E., Holst, M. & Lundmark, R. (2015). Cavin3 interacts with cavin1 and caveolin1 to increase surface dynamics of caveolae. Journal of Cell Science, 128(5), 979-991
Open this publication in new window or tab >>Cavin3 interacts with cavin1 and caveolin1 to increase surface dynamics of caveolae
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2015 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 128, no 5, p. 979-991Article in journal (Refereed) Published
Abstract [en]

Caveolae are invaginations of the cell surface thought to regulate membrane tension, signalling, adhesion and lipid homeostasis due to their dynamic behaviour ranging from stable surface association to dynamic rounds of fission and fusion with the plasma membrane. The caveolae coat is generated by oligomerisation of the membrane protein caveolin and the family of cavin proteins. Here, we show that cavin3 is targeted to caveolae by cavin1 where it interacts with the scaffolding domain of caveolin1 and promote caveolae dynamics. We found that the N-terminal region of cavin3 binds a trimer of the cavin1 N-terminus in competition with a homologous cavin2 region, showing that the cavins form distinct subcomplexes via their N-terminal regions. Our data shows that cavin3 is enriched at deeply invaginated caveolae and that loss of cavin3 in cells results in an increase of stable caveolae and a decrease of caveolae with short duration time at the membrane. We propose that cavin3 is recruited to the caveolae coat by cavin1 to interact with caveolin1 and regulate the duration time of caveolae at the plasma membrane.

Keywords
Cavin1, Cavin3, Caveolin1, Caveolae, EHD2
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-92497 (URN)10.1242/jcs.161463 (DOI)000350569900014 ()
Available from: 2014-08-27 Created: 2014-08-27 Last updated: 2018-06-07Bibliographically approved
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