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Larsson, Elin
Publications (10 of 27) Show all publications
Larsson, E., Morén, B., McMahon, K.-A., Parton, R. G. & Lundmark, R. (2023). Dynamin2 functions as an accessory protein to reduce the rate of caveola internalization. Journal of Cell Biology, 222(4), Article ID e202205122.
Open this publication in new window or tab >>Dynamin2 functions as an accessory protein to reduce the rate of caveola internalization
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2023 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 222, no 4, article id e202205122Article in journal (Refereed) Published
Abstract [en]

Caveolae are small membrane invaginations that generally are stably attached to the plasma membrane. Their release is believed to depend on the GTPase dynamin 2 (Dyn2), in analogy with its role in fission of clathrin-coated vesicles. The mechanistic understanding of caveola fission is, however, sparse. Here, we used microscopy-based tracking of individual caveolae in living cells to determine the role of Dyn2 in caveola dynamics. We report that Dyn2 stably associated with the bulb of a subset of caveolae, but was not required for formation or fission of caveolae. Dyn2-positive caveolae displayed longer plasma membrane duration times, whereas depletion of Dyn2 resulted in shorter duration times and increased caveola fission. The stabilizing role of Dyn2 was independent of its GTPase activity and the caveola stabilizing protein EHD2. Thus, we propose that, in contrast to the current view, Dyn2 is not a core component of the caveolae machinery, but rather functions as an accessory protein that restrains caveola internalization.

Place, publisher, year, edition, pages
Rockefeller University Press, 2023
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-208218 (URN)10.1083/jcb.202205122 (DOI)000978090900001 ()36729022 (PubMedID)2-s2.0-85153874757 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2017/735Swedish Research Council, 2017-04028Swedish Research Council, 2021-05117Swedish Cancer Society, 20 1230 PjFUmeå University
Available from: 2023-05-12 Created: 2023-05-12 Last updated: 2023-09-05Bibliographically approved
Hubert, M., Larsson, E., Liu, K. C. & Lundmark, R. (2022). Caveolae biogenesis and lipid sorting at the plasma membrane. In: Shiro Suetsugu (Ed.), Plasma membrane shaping: (pp. 219-228). Academic Press
Open this publication in new window or tab >>Caveolae biogenesis and lipid sorting at the plasma membrane
2022 (English)In: Plasma membrane shaping / [ed] Shiro Suetsugu, Academic Press, 2022, p. 219-228Chapter in book (Refereed)
Abstract [en]

The plasma membrane of many cell types, in particular, endothelia, smooth muscle cells, and adipocytes, contains numerous small invaginations termed caveolae. In nonmuscle cells, caveolae are formed by lipid-driven assembly of the integral membrane protein caveolin 1 (Cav1) and the peripherally attached protein cavin1. Accessory proteins such as Eps15 homology domain-containing 2 (EHD2) control the cell surface association of caveolae, together providing a unique invaginated membrane structure with distinct dynamics and protein and lipid compositions. These features enable caveolae to survey the plasma membrane integrity and to adjust membrane tension, and sort lipids according to the cellular requirements. Currently, characteristics of the protein and lipid interface of caveola are being unraveled, and this chapter is focused on the present knowledge of caveolae biogenesis and dynamics and describes methods that are being used to study the role of caveolae in lipid flux and lipid composition at the cell surface.

Place, publisher, year, edition, pages
Academic Press, 2022
Keywords
Caveolae, caveolin, cavin, cholesterol, dynamics, EHD2, fission, glycosphingolipids, lipids, scission
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-201754 (URN)10.1016/B978-0-323-89911-6.00017-0 (DOI)2-s2.0-85143309516 (Scopus ID)9780323899116 (ISBN)9780323899192 (ISBN)
Available from: 2022-12-30 Created: 2022-12-30 Last updated: 2023-03-24Bibliographically approved
Liu, K.-C., Pace, H., Larsson, E., Hossain, S., Kabedev, A., Shukla, A., . . . Lundmark, R. (2022). Membrane insertion mechanism of the caveola coat protein Cavin1. Proceedings of the National Academy of Sciences of the United States of America, 119(25), Article ID 2202295119.
Open this publication in new window or tab >>Membrane insertion mechanism of the caveola coat protein Cavin1
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2022 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 119, no 25, article id 2202295119Article in journal (Refereed) Published
Abstract [en]

Caveolae are small plasma membrane invaginations, important for control of membrane tension, signaling cascades, and lipid sorting. The caveola coat protein Cavin1 is essential for shaping such high curvature membrane structures. Yet, a mechanistic understanding of how Cavin1 assembles at the membrane interface is lacking. Here, we used model membranes combined with biophysical dissection and computational modeling to show that Cavin1 inserts into membranes. We establish that initial phosphatidylinositol (4, 5) bisphosphate [PI(4,5)P2]-dependent membrane adsorption of the trimeric helical region 1 (HR1) of Cavin1 mediates the subsequent partial separation and membrane insertion of the individual helices. Insertion kinetics of HR1 is further enhanced by the presence of flanking negatively charged disordered regions, which was found important for the coassembly of Cavin1 with Caveolin1 in living cells. We propose that this intricate mechanism potentiates membrane curvature generation and facilitates dynamic rounds of assembly and disassembly of Cavin1 at the membrane.

Place, publisher, year, edition, pages
Proceedings of the National Academy of Sciences, 2022
Keywords
caveolae, Cavin1, membrane curvature, membrane-shaping protein, protein-lipid interactions
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-203198 (URN)10.1073/pnas.2202295119 (DOI)000838706900008 ()2-s2.0-85133725056 (Scopus ID)
Funder
Swedish Research Council, 2018-05973European CommissionThe Kempe FoundationsSwedish Cancer SocietyWallenberg Foundations
Available from: 2023-01-18 Created: 2023-01-18 Last updated: 2023-01-18Bibliographically approved
Larsson, E., Hubert, M. & Lundmark, R. (2020). Analysis of protein and lipid interactions using liposome co-sedimentation assays. In: Cedric M. Blouin (Ed.), Caveolae: methods and protocols (pp. 119-127). Humana Press
Open this publication in new window or tab >>Analysis of protein and lipid interactions using liposome co-sedimentation assays
2020 (English)In: Caveolae: methods and protocols / [ed] Cedric M. Blouin, Humana Press, 2020, , p. 9p. 119-127Chapter in book (Refereed)
Abstract [en]

The dynamic assembly of proteins at the membrane interphase is key to many cell biological processes such as the generation and stabilization of caveolae at the cell surface via coat proteins. The liposome co-sedimentation assay has been widely used for studies of protein and lipid interactions and has provided important information about binding mechanisms, lipid-binding specificity, and curvature preference of proteins. Here, we describe this technique in detail and how it can be used as a tool to address the membrane-binding ability and lipid specificity of caveolae-associated proteins.

Place, publisher, year, edition, pages
Humana Press, 2020. p. 9
Series
Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029 ; 2169
Keywords
Caveolae coat, Cavin, Co-sedimentation, EHD2, Lipid specificity, Liposome pull down, Liposomes, Protein and lipid interactions, SUVs
National Category
Biophysics Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-197951 (URN)10.1007/978-1-0716-0732-9_11 (DOI)2-s2.0-85086686139 (Scopus ID)978-1-0716-0731-2 (ISBN)978-1-0716-0734-3 (ISBN)978-1-0716-0732-9 (ISBN)
Available from: 2022-07-08 Created: 2022-07-08 Last updated: 2023-03-24Bibliographically approved
Matthaeus, C., Lahmann, I., Kunz, S., Jonas, W., Melo, A. A., Lehmann, M., . . . Daumke, O. (2020). EHD2-mediated restriction of caveolar dynamics regulates cellular fatty acid uptake. Proceedings of the National Academy of Sciences of the United States of America, 117(13), 7471-7481
Open this publication in new window or tab >>EHD2-mediated restriction of caveolar dynamics regulates cellular fatty acid uptake
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2020 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 117, no 13, p. 7471-7481Article in journal (Refereed) Published
Abstract [en]

Eps15-homology domain containing protein 2 (EHD2) is a dynamin-related ATPase located at the neck of caveolae, but its physiological function has remained unclear. Here, we found that global genetic ablation of EHD2 in mice leads to increased lipid droplet size in fat tissue. This organismic phenotype was paralleled at the cellular level by increased fatty acid uptake via a caveolae- and CD36-dependent pathway that also involves dynamin. Concomitantly, elevated numbers of detached caveolae were found in brown and white adipose tissue lacking EHD2, and increased caveolar mobility in mouse embryonic fibroblasts. EHD2 expression itself was down-regulated in the visceral fat of two obese mouse models and obese patients. Our data suggest that EHD2 controls a cell-autonomous, caveolae-dependent fatty acid uptake pathway and imply that low EHD2 expression levels are linked to obesity.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2020
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-169888 (URN)10.1073/pnas.1918415117 (DOI)000523188100070 ()32170013 (PubMedID)2-s2.0-85082834169 (Scopus ID)
Available from: 2020-04-29 Created: 2020-04-29 Last updated: 2023-03-23Bibliographically approved
Hubert, M., Larsson, E. & Lundmark, R. (2020). Keeping in touch with the membrane; protein- and lipid-mediated confinement of caveolae to the cell surface. Biochemical Society Transactions, 48, 155-163
Open this publication in new window or tab >>Keeping in touch with the membrane; protein- and lipid-mediated confinement of caveolae to the cell surface
2020 (English)In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 48, p. 155-163Article, review/survey (Refereed) Published
Abstract [en]

Caveolae are small Omega-shaped invaginations of the plasma membrane that play important roles in mechanosensing, lipid homeostasis and signaling. Their typical morphology is characterized by a membrane funnel connecting a spherical bulb to the membrane. Membrane funnels (commonly known as necks and pores) are frequently observed as transient states during fusion and fission of membrane vesicles in cells. However, caveolae display atypical dynamics where the membrane funnel can be stabilized over an extended period of time, resulting in cell surface constrained caveolae. In addition, caveolae are also known to undergo flattening as well as short-range cycles of fission and fusion with the membrane, requiring that the membrane funnel closes or opens up, respectively. This mini-review considers the transition between these different states and highlights the role of the protein and lipid components that have been identified to control the balance between surface association and release of caveolae.

Place, publisher, year, edition, pages
PORTLAND PRESS LTD, 2020
Keywords
caveolae, caveolin, cholesterol, dynamics, EHD2, pacsin2
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-169355 (URN)10.1042/BST20190386 (DOI)000518382800015 ()32049332 (PubMedID)2-s2.0-85081069553 (Scopus ID)
Available from: 2020-04-07 Created: 2020-04-07 Last updated: 2023-03-23Bibliographically approved
Hubert, M., Larsson, E., Vegesna, N. V., Ahnlund, M., Johansson, A. I., Moodie, L. W. K. & Lundmark, R. (2020). Lipid accumulation controls the balance between surface connection and scission of caveolae. eLIFE, 9, Article ID e55038.
Open this publication in new window or tab >>Lipid accumulation controls the balance between surface connection and scission of caveolae
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2020 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 9, article id e55038Article in journal (Refereed) Published
Abstract [en]

Caveolae are bulb-shaped invaginations of the plasma membrane (PM) that undergo scission and fusion at the cell surface and are enriched in specific lipids. However, the influence of lipid composition on caveolae surface stability is not well described or understood. Accordingly, we inserted specific lipids into the cell PM via membrane fusion and studied their acute effects on caveolae dynamics. We demonstrate that sphingomyelin stabilizes caveolae to the cell surface, whereas cholesterol and glycosphingolipids drive caveolae scission from the PM. Although all three lipids accumulated specifically in caveolae, cholesterol and sphingomyelin were actively sequestered, whereas glycosphingolipids diffused freely. The ATPase EHD2 restricts lipid diffusion and counteracts lipid-induced scission. We propose that specific lipid accumulation in caveolae generates an intrinsically unstable domain prone to scission if not restrained by EHD2 at the caveolae neck. This work provides a mechanistic link between caveolae and their ability to sense the PM lipid composition.

Place, publisher, year, edition, pages
eLife Sciences Publications Ltd, 2020
National Category
Biochemistry and Molecular Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-172503 (URN)10.7554/eLife.55038 (DOI)000537207600001 ()32364496 (PubMedID)2-s2.0-85084964804 (Scopus ID)
Funder
Swedish Research Council, 2017-04028Swedish Cancer Society, CAN 2017/735Swedish Cancer Society, CAN2014/746The Kempe Foundations
Available from: 2020-07-02 Created: 2020-07-02 Last updated: 2020-07-02Bibliographically approved
Rodrigues, L., Schneider, F., Zhang, X., Larsson, E., Moodie, L. W. K., Dietz, H., . . . Hubert, M. (2019). Cellular uptake of self-assembled phytantriol-based hexosomes is independent of major endocytic machineries. Journal of Colloid and Interface Science, 553, 820-833
Open this publication in new window or tab >>Cellular uptake of self-assembled phytantriol-based hexosomes is independent of major endocytic machineries
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2019 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 553, p. 820-833Article in journal (Refereed) Published
Abstract [en]

Despite increasing interests in non-lamellar liquid crystalline dispersions, such as hexosomes, for drug delivery, little is known about their interactions with cells and mechanism of cell entry. Here we examine the cellular uptake of hexosomes based on phytantriol and mannide monooleate by HeLa cells using live cell microscopy in comparison to conventional liposomes. To investigate the importance of specific endocytosis pathways upon particle internalization, we silenced regulatory proteins of major endocytosis pathways using short interfering RNA. While endocytosis plays a significant role in liposome internalization, hexosomes are not taken up via endocytosis but through a mechanism that is dependent on cell membrane tension. Biophysical studies using biomembrane models highlighted that hexosomes have a high affinity for membranes and an ability to disrupt lipid layers. Our data suggest that direct biomechanical interactions of hexosomes with membrane lipids play a crucial role and that the unique morphology of hexosomes is vital for their membrane activity. Based on these results, we propose a mechanism, where hexosomes destabilize the bilayer, allowing them to "phase through" the membrane. Understanding parameters that influence the uptake of hexosomes is critical to establish them as carrier systems that can potentially deliver therapeutics efficiently to intracellular sites of action.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Hexosomes, Phytantriol, Mannide monooleate, Self-assembly, Nanostructure, Endocytosis, Cell take, Biomembrane models
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-164503 (URN)10.1016/j.jcis.2019.06.045 (DOI)000483454400086 ()31284226 (PubMedID)2-s2.0-85068359801 (Scopus ID)
Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2023-03-23Bibliographically approved
Yau, W.-L., Nguyen-Dinh, V., Larsson, E., Lindquist, R., Överby, A. K. & Lundmark, R. (2019). Model System for the Formation of Tick-Borne Encephalitis Virus Replication Compartments without Viral RNA Replication. Journal of Virology, 93(18), Article ID e00292-19.
Open this publication in new window or tab >>Model System for the Formation of Tick-Borne Encephalitis Virus Replication Compartments without Viral RNA Replication
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2019 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 93, no 18, article id e00292-19Article in journal (Refereed) Published
Abstract [en]

Flavivirus is a positive-sense, single-stranded RNA viral genus, with members causing severe diseases in humans such as tick-borne encephalitis, yellow fever, and dengue fever. Flaviviruses are known to cause remodeling of intracellular membranes into small cavities, where replication of the viral RNA takes place. Nonstructural (NS) proteins are not part of the virus coat and are thought to participate in the formation of these viral replication compartments (RCs). Here, we used tick-borne encephalitis virus (TBEV) as a model for the flaviviruses and developed a stable human cell line in which the expression of NS proteins can be induced without viral RNA replication. The model system described provides a novel and benign tool for studies of the viral components under controlled expression levels. We show that the expression of six NS proteins is sufficient to induce infection-like dilation of the endoplasmic reticulum (ER) and the formation of RC-like membrane invaginations. The NS proteins form a membrane-associated complex in the ER, and electron tomography reveals that the dilated areas of the ER are closely associated with lipid droplets and mitochondria. We propose that the NS proteins drive the remodeling of ER membranes and that viral RNA, RNA replication, viral polymerase, and TBEV structural proteins are not required. IMPORTANCE TBEV infection causes a broad spectrum of symptoms, ranging from mild fever to severe encephalitis. Similar to other flaviviruses, TBEV exploits intracellular membranes to build RCs for viral replication. The viral NS proteins have been suggested to be involved in this process; however, the mechanism of RC formation and the roles of individual NS proteins remain unclear. To study how TBEV induces membrane remodeling, we developed an inducible stable cell system expressing the TBEV NS polyprotein in the absence of viral RNA replication. Using this system, we were able to reproduce RC-like vesicles that resembled the RCs formed in flavivirus-infected cells, in terms of morphology and size. This cell system is a robust tool to facilitate studies of flavivirus RC formation and is an ideal model for the screening of antiviral agents at a lower biosafety level.

Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY, 2019
Keywords
Flaviviridae, Flp-In cell line, NS4B, flavivirus, replication compartment, replication vesicles, tick-borne cephalitis virus
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-164506 (URN)10.1128/JVI.00292-19 (DOI)000483427300003 ()31243132 (PubMedID)2-s2.0-85071714281 (Scopus ID)
Available from: 2019-11-22 Created: 2019-11-22 Last updated: 2023-04-25Bibliographically 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)2-s2.0-85055771831 (Scopus ID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research The Kempe Foundations
Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2023-03-23Bibliographically approved
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