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J Biol Chem. 2017 Aug 25;292(34):14292-14307. doi: 10.1074/jbc.M117.791400. Epub 2017 Jul 11.

Phosphatidylserine dictates the assembly and dynamics of caveolae in the plasma membrane.

Author information

1
From the Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada.
2
the Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G1X8, Canada.
3
the Department of Respiratory Medicine, Saitama Medical University, Moroyama, Saitama 3500495, Japan.
4
the Department of Integrative Biology, University of Colorado Denver, Denver, Colorado 80204.
5
the Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
6
the Institute for Molecular Bioscience and Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, Queensland 4072, Australia.
7
The Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
8
the Department of Oral Biology, School of Dental Medicine, the State University of New York at Buffalo, Buffalo, New York 14214, and.
9
From the Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada, fairng@smh.ca.
10
the Institute for Biomedical Engineering and Science Technology (iBEST), Ryerson University and St. Michael's Hospital, Toronto, Ontario M5B 2K3, Canada.

Abstract

Caveolae are bulb-shaped nanodomains of the plasma membrane that are enriched in cholesterol and sphingolipids. They have many physiological functions, including endocytic transport, mechanosensing, and regulation of membrane and lipid transport. Caveola formation relies on integral membrane proteins termed caveolins (Cavs) and the cavin family of peripheral proteins. Both protein families bind anionic phospholipids, but the precise roles of these lipids are unknown. Here, we studied the effects of phosphatidylserine (PtdSer), phosphatidylinositol 4-phosphate (PtdIns4P), and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) on caveolar formation and dynamics. Using live-cell, single-particle tracking of GFP-labeled Cav1 and ultrastructural analyses, we compared the effect of PtdSer disruption or phosphoinositide depletion with caveola disassembly caused by cavin1 loss. We found that PtdSer plays a crucial role in both caveola formation and stability. Sequestration or depletion of PtdSer decreased the number of detectable Cav1-GFP puncta and the number of caveolae visualized by electron microscopy. Under PtdSer-limiting conditions, the co-localization of Cav1 and cavin1 was diminished, and cavin1 degradation was increased. Using rapamycin-recruitable phosphatases, we also found that the acute depletion of PtdIns4P and PtdIns(4,5)P2 has minimal impact on caveola assembly but results in decreased lateral confinement. Finally, we show in a model of phospholipid scrambling, a feature of apoptotic cells, that caveola stability is acutely affected by the scrambling. We conclude that the predominant plasmalemmal anionic lipid PtdSer is essential for proper Cav clustering, caveola formation, and caveola dynamics and that membrane scrambling can perturb caveolar stability.

KEYWORDS:

TIRF microscopy; caveolae; microscopic imaging; phosphatidylinositol signaling; phosphatidylserine; phosphoinositides; single-particle analysis

PMID:
28698382
PMCID:
PMC5572903
DOI:
10.1074/jbc.M117.791400
[Indexed for MEDLINE]
Free PMC Article
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