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Lundmark, Richard
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Publications (10 of 65) 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
Pulkkinen, L. I., Barrass, S. V., Lindgren, M., Pace, H., Överby, A. K., Anastasina, M., . . . Butcher, S. J. (2023). Simultaneous membrane and RNA binding by tick-borne encephalitis virus capsid protein. PLoS Pathogens, 19(2), Article ID e1011125.
Open this publication in new window or tab >>Simultaneous membrane and RNA binding by tick-borne encephalitis virus capsid protein
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2023 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 19, no 2, article id e1011125Article in journal (Refereed) Published
Abstract [en]

Tick-borne encephalitis virus is an enveloped, pathogenic, RNA virus in the family Flaviviridae, genus Flavivirus. Viral particles are formed when the nucleocapsid, consisting of an RNA genome and multiple copies of the capsid protein, buds through the endoplasmic reticulum membrane and acquires the viral envelope and the associated proteins. The coordination of the nucleocapsid components to the sites of assembly and budding are poorly understood. Here, we investigate the interactions of the wild-type and truncated capsid proteins with membranes with biophysical methods and model membrane systems. We show that capsid protein initially binds membranes via electrostatic interactions with negatively-charged lipids, which is followed by membrane insertion. Additionally, we show that membrane-bound capsid protein can recruit viral genomic RNA. We confirm the biological relevance of the biophysical findings by using mass spectrometry to show that purified virions contain negatively-charged lipids. Our results suggest that nucleocapsid assembly is coordinated by negatively-charged membrane patches on the endoplasmic reticulum and that the capsid protein mediates direct contacts between the nucleocapsid and the membrane.

Place, publisher, year, edition, pages
Public Library of Science, 2023
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-205497 (URN)10.1371/journal.ppat.1011125 (DOI)000966733300001 ()36787339 (PubMedID)2-s2.0-85149054055 (Scopus ID)
Available from: 2023-03-14 Created: 2023-03-14 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
Fryklund, C., Neuhaus, M., Morén, B., Borreguero-Muñoz, A., Lundmark, R. & Stenkula, K. G. (2022). Expansion of the Inguinal Adipose Tissue Depot Correlates With Systemic Insulin Resistance in C57BL/6J Mice. Frontiers in Cell and Developmental Biology, 10, Article ID 942374.
Open this publication in new window or tab >>Expansion of the Inguinal Adipose Tissue Depot Correlates With Systemic Insulin Resistance in C57BL/6J Mice
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2022 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 10, article id 942374Article in journal (Refereed) Published
Abstract [en]

To accommodate surplus energy, the adipose tissue expands by increasing adipocyte size (hypertrophy) and number (hyperplasia). The presence of hypertrophic adipocytes is a key characteristic of adipose tissue dysfunction. High-fat diet (HFD) fed C57BL/6J mice are a commonly used model to study obesity and obesity-related complications. In the present study, we have characterized adipose plasticity, at both the cellular and tissue level, by examining the temporal development of systemic insulin resistance and adiposity in response to HFD-feeding for 4, 8, and 12 weeks (4w, 8w, and 12w). Within the same time frame, we examined systemic metabolic flexibility and adipose plasticity when switching from HFD- to chow-diet during the last 2 weeks of diet intervention (referred to as the reverse (REV) group: 4wREV (2w HFD+2w chow), 8wREV (6w HFD+2w chow), 12wREV (10w HFD+2w chow)). In response to HFD-feeding over time, the 12w group had impaired systemic insulin sensitivity compared to both the 4w and 8w groups, accompanied by an increase in hypertrophic inguinal adipocytes and liver triglycerides. After reversing from HFD- to chow-feeding, most parameters were completely restored to chow control levels for 4wREV and 8wREV groups. In contrast, the 12wREV group had a significantly increased number of hypertrophic adipocytes, liver triglycerides accumulation, and impaired systemic insulin sensitivity compared to chow-fed mice. Further, image analysis at the single-cell level revealed a cell-size dependent organization of actin filaments for all feeding conditions. Indeed, the impaired adipocyte size plasticity in the 12wREV group was accompanied by increased actin filamentation and reduced insulin-stimulated glucose uptake compared with chow-fed mice. In summary, these results demonstrate that the C57BL/6J HFD-feeding model has a large capacity to restore adipocyte cell size and systemic insulin sensitivity, and that a metabolic tipping point occurs between 8 and 12w of HFD-feeding where this plasticity deteriorates. We believe these findings provide substantial understanding of C57BL/6J mice as an obesity model, and that an increased pool of hypertrophic ING adipocytes could contribute to aggravated insulin resistance.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2022
Keywords
adipocytes, cell size, cytoskeleton, glucose transport, insulin, obesity
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-199895 (URN)10.3389/fcell.2022.942374 (DOI)000855945600001 ()36158197 (PubMedID)2-s2.0-85138356642 (Scopus ID)
Funder
Swedish Research Council, 2019-00978Swedish Foundation for Strategic Research, IRC15-0067Novo Nordisk, NNF20OC0063659DiabetesfondenThe Crafoord Foundation
Available from: 2022-10-03 Created: 2022-10-03 Last updated: 2022-10-03Bibliographically 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
Wang, T., Sarwar, M., Whitchurch, J. B., Collins, H. M., Green, T., Semenas, J., . . . Persson, J. L. (2022). PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer. Frontiers in Cell and Developmental Biology, 10, Article ID 798590.
Open this publication in new window or tab >>PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer
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2022 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 10, article id 798590Article in journal (Refereed) Published
Abstract [en]

PIP5K1α has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1α in this process. Here, we show that siRNA-mediated knockdown of PIP5K1α and blockade of PIP5K1α action using its small molecule inhibitor ISA-2011B suppress growth and invasion of CRPC cells. We demonstrate that targeted deletion of the N-terminal domain of PIP5K1α in CRPC cells results in reduced growth and migratory ability of cancer cells. Further, the xenograft tumors lacking the N-terminal domain of PIP5K1α exhibited reduced tumor growth and aggressiveness in xenograft mice as compared to that of controls. The N-terminal domain of PIP5K1α is required for regulation of mRNA expression and protein stability of PIP5K1α. This suggests that the expression and oncogenic activity of PIP5K1α are in part dependent on its N-terminal domain. We further show that PIP5K1α acts as an upstream regulator of the androgen receptor (AR) and AR target genes including CDK1 and MMP9 that are key factors promoting growth, survival and invasion of PCa cells. ISA-2011B exhibited a significant inhibitory effect on AR target genes including CDK1 and MMP9 in CRPC cells with wild-type PIP5K1α and in CRPC cells lacking the N-terminal domain of PIP5K1α. These results indicate that the growth of PIP5K1α-dependent tumors is in part dependent on the integrity of the N-terminal sequence of this kinase. Our study identifies a novel functional mechanism involving PIP5K1α, confirming that PIP5K1α is an intriguing target for cancer treatment, especially for treatment of CRPC.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2022
Keywords
androgen receptor (AR), castration-resistant prostate cancer (CRPC), cyclin-dependent kinase (CDK), matrix metalloproteinases 9 (MMP9) PIP5K1α, phosphatidylinositol 4-phosphate 5 kinase (PIP5K1α), targeted therapy
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-193614 (URN)10.3389/fcell.2022.798590 (DOI)000780059400001 ()35386201 (PubMedID)2-s2.0-85128078251 (Scopus ID)
Funder
EU, Horizon 2020, 721297Swedish Childhood Cancer Foundation, TJ2015-0097Swedish Cancer Society, CAN-2017-381Swedish Research Council, 2019-01318The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2013-5595The Kempe FoundationsCancerforskningsfonden i Norrland
Available from: 2022-04-07 Created: 2022-04-07 Last updated: 2023-05-23Bibliographically approved
Wright, L., Joyce, P., Barnes, T. J., Lundmark, R., Bergstrom, C. A. S., Hubert, M. & Prestidge, C. A. (2021). A Comparison of Chitosan, Mesoporous Silica and Poly(lactic-co-glycolic) Acid Nanocarriers for Optimising Intestinal Uptake of Oral Protein Therapeutics. Journal of Pharmaceutical Sciences, 110(1), 217-227
Open this publication in new window or tab >>A Comparison of Chitosan, Mesoporous Silica and Poly(lactic-co-glycolic) Acid Nanocarriers for Optimising Intestinal Uptake of Oral Protein Therapeutics
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2021 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 110, no 1, p. 217-227Article in journal (Refereed) Published
Abstract [en]

Efficacious oral delivery of therapeutic proteins remains challenging and nanoparticulate approaches are gaining interest for enhancing their permeability. In this study, we explore the ability for three comparably sized nanocarriers, with diverse physicochemical properties [i.e., chitosan (CSNP), mesoporous silica nanoparticles (MSNP) and poly(lactic-co-glycolic) acid (PLGA-NP)], to successfully facilitate epithelial uptake of a model protein, ovalbumin (OVA). We report the effect of nanoparticle surface chemistry and nanostructure on protein release, cell toxicity and the uptake mechanism in a Madin Darby Canine Kidney (MDCK) cell model of the intestinal epithelium. All nanocarriers exhibited bi-phasic OVA release kinetics with sustained and incomplete release after 4 days, and more pronounced release from MSNP than either polymeric nanocarriers. CSNP and MSNP displayed the highest cellular uptake, however CSNP was prone to significant dose-dependent toxicity attributed to the cationic surface charge. Approximately 25% of MSNP uptake was governed by a clathrin-independent endocytic mechanism, while CSNP and PLGA-NP uptake was not controlled via any endocytic mechanisms investigated herein. Furthermore, endosomal localisation was observed for CSNP and MSNP, but not for PLGA-NP. These findings may assist in the optimal choice and engineering of nanocarriers for specific intestinal permeation enhancement for oral protein delivery.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Chitosan, Macromolecular drug delivery, MDCK cells, Nanoparticle(s), Oral drug delivery, Permeability, Physicochemical properties, Polyglycolic acid (PLGA), Protein delivery, Silica
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:umu:diva-178693 (URN)10.1016/j.xphs.2020.09.026 (DOI)000600571800022 ()32979363 (PubMedID)2-s2.0-85092227207 (Scopus ID)
Available from: 2021-01-14 Created: 2021-01-14 Last updated: 2023-03-23Bibliographically approved
Pastula, A. & Lundmark, R. (2021). Induction of Epithelial-mesenchymal Transition in MDCK II Cells. Bio-protocol, 11(3), Article ID e3903.
Open this publication in new window or tab >>Induction of Epithelial-mesenchymal Transition in MDCK II Cells
2021 (English)In: Bio-protocol, E-ISSN 2331-8325, Vol. 11, no 3, article id e3903Article in journal (Refereed) Published
Abstract [en]

Epithelial-mesenchymal transition (EMT) is a reversible process of epithelial cell transdifferentiation into a mesenchymal cell, that enables initiation of cell migration. EMT plays an important role in embryonic development, tissue repair and cancer metastasis. Better understanding of cellular and molecular events during EMT will not only provide novel insights on how mammalian organism develops and how epithelial tissues regenerate, but also can identify novel therapeutic targets for cancer therapy. Here we aim to provide a detailed protocol on how to induce EMT in Madin-Darby Canine Kidney (MDCK) II epithelial cell line and perform immunofluorescent staining on EMT-induced cells.

Place, publisher, year, edition, pages
Bio-protocol, 2021
Keywords
Epithelial-mesenchymal transition, MDCK cells, Hepatocyte growth factor, Epithelial plasticity, EMT, Mesenchymal cell differentiation from epithelial cell
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-187355 (URN)10.21769/BioProtoc.3903 (DOI)000616641600003 ()33732790 (PubMedID)2-s2.0-85116018142 (Scopus ID)
Funder
Swedish Cancer Society, CAN2017/735
Available from: 2021-09-09 Created: 2021-09-09 Last updated: 2023-03-24Bibliographically 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
Parton, R. G., del Pozo, M. A., Vassilopoulos, S., Nabi, I. R., Le Lay, S., Lundmark, R., . . . Lamaze, C. (2020). Caveolae: The FAQs. Paper presented at EMBO Workshop – Caveolae and nanodomains: Translating structural principles and dynamics into function, 12–16 May 2019, Le Pouliguen, France. Traffic: the International Journal of Intracellular Transport, 21(1), 181-185
Open this publication in new window or tab >>Caveolae: The FAQs
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2020 (English)In: Traffic: the International Journal of Intracellular Transport, ISSN 1398-9219, E-ISSN 1600-0854, Vol. 21, no 1, p. 181-185Article in journal, Editorial material (Refereed) Published
Abstract [en]

Caveolae are an abundant, but enigmatic, plasma membrane feature of vertebrate cells. In this brief commentary, the authors attempt to answer some key questions related to the formation and function of caveolae based on round‐table discussions at the first EMBO Workshop on Caveolae held in France in May 2019.

Place, publisher, year, edition, pages
John Wiley & Sons, 2020
Keywords
caveolae, caveolins, cavins, EHD2, endocytosis, lipodystrophy, membrane, muscular dystrophy
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-164619 (URN)10.1111/tra.12689 (DOI)000485946300001 ()31448516 (PubMedID)2-s2.0-85072019904 (Scopus ID)
Conference
EMBO Workshop – Caveolae and nanodomains: Translating structural principles and dynamics into function, 12–16 May 2019, Le Pouliguen, France
Available from: 2019-11-12 Created: 2019-11-12 Last updated: 2023-03-24Bibliographically approved
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