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Holst, Mikkel R.
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Publications (8 of 8) 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
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
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
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
Francis, M. K., Holst, M. R., Vidal-Quadras, M., Henriksson, S., Santarella-Mellwig, R., Sandblad, L. & Lundmark, R. (2015). Endocytic membrane turnover at the leading edge is driven by a transient interaction between Cdc42 and GRAF1. Journal of Cell Science, 128(22), 4183-4195
Open this publication in new window or tab >>Endocytic membrane turnover at the leading edge is driven by a transient interaction between Cdc42 and GRAF1
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2015 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 128, no 22, p. 4183-4195Article in journal (Refereed) Published
Abstract [en]

Changes in cell morphology require coordination of plasma membrane turnover and cytoskeleton dynamics, processes that are regulated by Rho GTPases. Here, we describe how a direct interaction between the Rho GTPase Cdc42 and the GTPase activating protein (GAP) GRAF1, facilitate rapid cell surface turnover at the leading edge. Both Cdc42 and GRAF1 were required for fluid phase uptake and regulated the generation of transient GRAF1-coated endocytic carriers, distinct from clathrin coated vesicles. GRAF1 was found to transiently assemble at discrete Cdc42-enriched punctae at the plasma membrane resulting in a corresponding decrease in Cdc42 microdomain association. However, Cdc42 captured in its active state was, via a GAP domain mediated interaction, localised together with GRAF1 on accumulated internal structures derived from the cell surface. Correlative fluorescence and electron tomography microscopy revealed that these structures were clusters of small membrane carriers affected in their endosomal processing. We conclude that a transient interaction between Cdc42 and GRAF1 drives endocytic turnover and controls the transition essential for endosomal maturation of plasma membrane internalised by this mechanism.

National Category
Biochemistry and Molecular Biology Cell Biology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-111228 (URN)10.1242/jcs.174417 (DOI)000366314900017 ()26446261 (PubMedID)
Available from: 2015-11-11 Created: 2015-11-10 Last updated: 2018-06-07Bibliographically approved
Nygård Skalman, L., Holst, M. R. & Lundmark, R.Endocytic response to the pore-forming toxin listeriolysin O.
Open this publication in new window or tab >>Endocytic response to the pore-forming toxin listeriolysin O
(English)Manuscript (preprint) (Other academic)
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-134046 (URN)
Available from: 2017-04-25 Created: 2017-04-25 Last updated: 2018-06-09
Vidal-Quadras, M., Holst, M. R., Francis, M. K., Peränen, J. & Lundmark, R.Endocytic turnover of Rab8 controls cell polarisation.
Open this publication in new window or tab >>Endocytic turnover of Rab8 controls cell polarisation
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(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology Cell Biology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-111222 (URN)
Available from: 2015-11-11 Created: 2015-11-10 Last updated: 2018-06-07
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