Deletion of Cavin/PTRF Causes Global Loss of Caveolae, Dyslipidemia, and Glucose Intolerance

Liu, Libin; Brown, Dennis; McKee, Mary; LeBrasseur, Nathan K.; Yang, Dan; Albrecht, Kenneth H.; Ravid, Katya; Pilch, Paul F.

doi:10.1016/j.cmet.2008.07.008

Cited by 327 publications

(364 citation statements)

References 47 publications

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“…As a final step in quantitatively characterizing Cav1 dynamics, we down-regulated cavin1, a crucial regulator of caveolar formation (16,33). As confirmed in Fig.…”

Section: Diffusional Analysis Of Cav1-gfp Features In Untreated Cellsmentioning

confidence: 73%

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

Hirama

Das

Yang

et al. 2017

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerCaveolae 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)P 2 ) 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)P 2 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.

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“…As a final step in quantitatively characterizing Cav1 dynamics, we down-regulated cavin1, a crucial regulator of caveolar formation (16,33). As confirmed in Fig.…”

Section: Diffusional Analysis Of Cav1-gfp Features In Untreated Cellsmentioning

confidence: 73%

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

Hirama

Das

Yang

et al. 2017

Journal of Biological Chemistry

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“…After caveolins have trafficked to the plasma membrane, multimeric cavin complexes in the cytosol are recruited to the cytoplasmic surface of caveolae, where they stabilize caveolins (22,36). Among the cavins, cavin 1 is most critical for stabilization of caveolins and caveolae biogenesis (25,26,37). We therefore hypothesized that ablation of Fgf13 affected the relative distribution of cavin 1 and led to stabilization of caveolae.…”

Section: Fgf13 Regulates the Distribution Of Cavin 1 Between The Plasmamentioning

confidence: 99%

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Wei

Sinden

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The fibroblast growth factor (FGF) homologous factor FGF13, a noncanonical FGF, has been best characterized as a voltage-gated Na + channel auxiliary subunit. Other cellular functions have been suggested, but not explored. In inducible, cardiac-specific Fgf13 knockout mice, we found-even in the context of the expected reduction in Na + channel current-an unanticipated protection from the maladaptive hypertrophic response to pressure overload. To uncover the underlying mechanisms, we searched for components of the FGF13 interactome in cardiomyocytes and discovered the complete set of the cavin family of caveolar coat proteins. Detailed biochemical investigations showed that FGF13 acts as a negative regulator of caveolae abundance in cardiomyocytes by controlling the relative distribution of cavin 1 between the sarcolemma and cytosol. In cardiac-specific Fgf13 knockout mice, cavin 1 redistribution to the sarcolemma stabilized the caveolar structural protein caveolin 3. The consequent increase in caveolae density afforded protection against pressure overload-induced cardiac dysfunction by two mechanisms: (i) enhancing cardioprotective signaling pathways enriched in caveolae, and (ii) increasing the caveolar membrane reserve available to buffer membrane tension. Thus, our results uncover unexpected roles for a FGF homologous factor and establish FGF13 as a regulator of caveolae-mediated mechanoprotection and adaptive hypertrophic signaling. (1), share a core domain with homology to canonical FGFs, but FHFs are not secreted, do not bind or activate FGF receptors, and do not function as growth factors (2). Instead, FHFs bind directly to voltage-gated Na + channels, modulating channel gating and trafficking (3, 4). Widely expressed in the brain (1), FHFs have been implicated in neurologic diseases such as spinocerebellar ataxia 27, caused by missense mutations in FGF14 that diminish Na + channel current, disrupt channel localization, and impair neuronal excitability (5-7).In addition to their broad distribution in the central nervous system, FHFs are expressed in the mammalian heart (1). Their roles in regulating cardiac function, however, have only been recently investigated. We showed that FGF13, the predominant FHF in rodent heart and a common transcript in human heart (8), directly binds to the C terminus of cardiac Na V 1.5 Na + channels, and thereby regulates current density and conduction velocity by affecting channel gating and surface expression (9). Similarly, mutations that disrupt interaction between Na V 1.5 and FGF12, the major human cardiac FHF, have been linked to lifethreatening arrhythmia syndromes (8, 10). In addition to regulating Na + channels, FHFs can modulate voltage-gated Ca 2+ channels (11, 12). Fgf13 knockdown in adult rodent ventricular cardiomyocytes decreased Ca V 1.2 current density, perturbed Ca V 1.2 localization at the dyad, and thereby affected Ca 2+ -induced Ca 2+ release (11). Because previous studies were conducted in cultured cardiomyocytes, however, the in vivo roles for FHFs in ...

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“…The functions of caveolins are closely linked to a family of cytoplasmic proteins termed cavins (Hill et al 2008;Bastiani et al 2009;Hansen et al 2009;McMahon et al 2009). PTRF/ cavin-1 is essential for the formation of caveolae (Hill et al 2008;Liu et al 2008) and, like caveolin, has been shown to be associated with LD function and lipid storage in cultured adipocytes (Aboulaich et al 2006), mice (Liu et al 2008), and human patients (Hayashi et al 2009;Rajab et al 2010). …”

Section: Interactions With Caveolae Caveolins and Cavinsmentioning

confidence: 99%

Not Just Fat: The Structure and Function of the Lipid Droplet

Fujimoto

Parton²

2011

Cold Spring Harbor Perspectives in Biology

401

336

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Lipid droplets (LDs) are independent organelles that are composed of a lipid ester core and a surface phospholipid monolayer. Recent studies have revealed many new proteins, functions, and phenomena associated with LDs. In addition, a number of diseases related to LDs are beginning to be understood at the molecular level. It is now clear that LDs are not an inert store of excess lipids but are dynamically engaged in various cellular functions, some of which are not directly related to lipid metabolism. Compared to conventional membrane organelles, there are still many uncertainties concerning the molecular architecture of LDs and how each function is placed in a structural context. Recent findings and remaining questions are discussed.

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Deletion of Cavin/PTRF Causes Global Loss of Caveolae, Dyslipidemia, and Glucose Intolerance

Cited by 327 publications

References 47 publications

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

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

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Not Just Fat: The Structure and Function of the Lipid Droplet

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