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

Hirama, Takashi; Das, Raj Kumar; Yang, Yanbo; Ferguson, Charles; Won, Amy; Yip, Christopher M.; Kay, Jason G.; Grinstein, Sergio; Parton, Robert G.; Fairn, Gregory D.

doi:10.1074/jbc.m117.791400

Cited by 74 publications

(62 citation statements)

References 63 publications

(89 reference statements)

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“…High PS concentration is a hallmark of the cytosolic leaflet of the PM and is important for diverse cellular processes, from establishment of cell polarity, signaling and cytoskeleton organization to control of endocytosis and caveolae formation (Fairn et al, 2011;Sun and Drubin, 2013;Takano et al, 2008;Hirama et al, 2017). Identification of proteins that specifically transport PS to the PM in yeast and in mammalian cells represented an important step towards understanding how this PS enrichment is achieved (Maeda et al, 2013;Chung et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Osh6 requires Ist2 for localization to the ER-PM contacts and efficient phosphatidylserine transport

D’Ambrosio

Albanèse

Lipp

et al. 2020

Preprint

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Osh6 and Osh7 are lipid transfer proteins (LTPs) that transport phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM). High PS level at the PM is key for many cellular functions. Intriguingly, Osh6/7 localize to ER-PM contact sites, although they lack membrane-targeting motifs, in contrast to multidomain LTPs that both bridge membranes and convey lipids. We show that Osh6 localization to contact sites depends on its interaction with the cytosolic tail of the ER-PM tether Ist2, a homologue of TMEM16 proteins. We identify a motif in the Ist2 tail, conserved in yeasts, as the Osh6-binding region, and we map an Ist2-binding surface on Osh6. Mutations in the Ist2 tail phenocopy osh6D osh7D deletion: they decrease cellular PS levels, and block PS transport to the PM. Our study unveils an unexpected partnership between a TMEM16-like protein and a soluble LTP, which together mediate lipid transport at contact sites.

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Section: Discussionmentioning

confidence: 99%

Osh6 requires Ist2 for localization to the ER-PM contacts and efficient phosphatidylserine transport

D’Ambrosio

Albanèse

Lipp

et al. 2020

Preprint

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“…In view of the PtdSer-binding specificity via the cavin UC1 domain that is required for caveola stability and the role of PtdSer in caveola formation 35 , we next analysed whether PtdSer levels determined CAV1/cavin1 association. PSA3 cells generate less endogenous PtdSer when grown in medium containing dialyzed fetal bovine serum (DFBS), but PtdSer can be restored to near control levels by 10 µM ethanolamine (Etn) supplementation [16][17][18][19][20]36 .…”

Section: Association Of Caveolin and Cavin1 Requires Distinct Ptdser mentioning

confidence: 99%

Dissecting the nanoscale lipid profile of caveolae

Zhou

Ariotti

et al. 2020

Preprint

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words)Caveolae are specialized domains of the vertebrate cell surface with a well-defined morphology and crucial roles in cell migration and mechanoprotection. Unique compositions of proteins and lipids determine membrane architectures. The precise caveolar lipid profile and the roles of the major caveolar structural proteins, caveolins and cavins, in selectively sorting lipids have not been defined. Here we used quantitative nanoscale lipid mapping together with molecular dynamic simulations to define the caveolar lipid profile. We show that caveolin1 (CAV1) and cavin1 individually sort distinct plasma membrane lipids. Intact caveolar structures composed of both CAV1 and cavin1 further generate a unique lipid nanoenvironment. The caveolar lipid sorting capability includes selectivities for lipid headgroups and acyl chains. Because lipid headgroup metabolism and acyl chain remodelling are tightly regulated, this selective lipid sorting may allow caveolae to act as transit hubs to direct communications among lipid metabolism, vesicular trafficking and signalling.Caveolae are a striking morphological feature of the plasma membrane of many vertebrate cells. Caveolae have been implicated in mechanoprotection, endocytosis, signal transduction and lipid regulation 1-6 . The characteristic morphology of caveolae, with a bulb connected to the plasma membrane by a highly-curved neck, is generated by integral membrane proteins termed caveolins and by lipid binding peripheral membrane proteins, the cavins 7-14 .Specifically, caveolin-1 (CAV1) and caveolin-3 (CAV3, in striated muscle) and cavin1 (or polymerase I and transcript release factor, PTRF) are essential for caveola formation 7,10 .Another set of key caveolar components comprise the plasma membrane (PM) lipids. While biophysical studies have consistently suggested that the lateral distribution of lipids determines and/or responds to changing membrane morphology, our understanding of the lipid composition of caveolae and how this contributes to caveola formation, function, and disassembly, is still relatively primitive. A detailed molecular understanding of the lipid constituents of caveolae, defined both by their headgroups and acyl chains, is crucial for understanding the formation of caveolae, as well as their disassembly, processes that are crucial for caveola function. Moreover, caveolae can provide a paradigm for understanding how local concentrations of specific lipid species contribute to membrane morphogenesis.

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“…PC is also a prominent phospholipid in caveolae (Huot et al, 2010;Pike et al, 2005;Smart et al, 1999), while PS has been found to be abundant in the cytoplasmic leaflet of caveolae (Fairn et al, 2011;Pike et al, 2005). The depletion of PS was shown to result in the loss of caveolar morphology (Hirama et al, 2017). The main fatty acids of caveolar phospholipids are oleic acid (C18:1), palmitic acid (C16:0) (Cai et al, 2013;Huot et al, 2010), and stearic acid (C18:0) (Cai et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Regulation of caveolae through cholesterol-depletion dependent tubulation by PACSIN2/Syndapin II

Amir

Takemura

Oono-Yakura

et al. 2020

Preprint

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The membrane shaping ability of PACSIN2 via its FCH-BAR (F-BAR) domain has beenshown to be essential for caveolar morphogenesis, presumably through the shaping of the caveolar neck. Caveolar membrane contains abundant levels of cholesterol. However, the role of cholesterol in PACSIN2-mediated membrane deformation remains unclear. We show that the binding of PACSIN2 to the membrane could be negatively regulated by the amount of cholesterol in the membrane. We prepared a reconstituted membrane based on the lipid composition of caveolae. The reconstituted membrane with cholesterol had a weaker affinity to the F-BAR domain of PACSIN2 than the membrane without cholesterol, presumably due to a decrease in electrostatic charge density. Consistently, the acute depletion of cholesterol from the plasma membrane resulted in the appearance of PACSIN2-localized tubules with caveolin-1 at their tips, suggesting that the presence of cholesterol inhibited the prominent membrane tubulation by PACSIN2. The tubules induced by PACSIN2 were suggested to be an intermediate of caveolae endocytosis. Consistently, the removal of caveolae from the plasma membrane upon cholesterol depletion was diminished in the cells deficient in PACSIN2. These data suggested that PACSIN2 mediated the caveolae internalization dependently on the amount of cholesterol at the plasma membrane, providing a possible mechanism for the cholesterol-dependent regulation of caveolae.

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

Cited by 74 publications

References 63 publications

Osh6 requires Ist2 for localization to the ER-PM contacts and efficient phosphatidylserine transport

Osh6 requires Ist2 for localization to the ER-PM contacts and efficient phosphatidylserine transport

Dissecting the nanoscale lipid profile of caveolae

Regulation of caveolae through cholesterol-depletion dependent tubulation by PACSIN2/Syndapin II

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