EHD2 regulates caveolar dynamics via ATP-driven targeting and oligomerization

Morén, Björn; Shah, Claudio; Howes, Mark T.; Schieber, Nicole L.; McMahon, Harvey T.; Parton, Robert G.; Daumke, Oliver; Lundmark, Richard

doi:10.1091/mbc.e11-09-0787

Cited by 177 publications

(272 citation statements)

References 47 publications

(85 reference statements)

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“…Previous studies have shown that caveolae are largely immobile in the plane of the membrane in unstimulated cells (5,9,26,27). To confirm that our HeLa/Cav1-GFP cells behaved similarly, we used rapid time-lapse microscopy (25 acquisitions/s for a total of 20 s) and subsequently analyzed the mobility and trajectory of detected features using single-particle tracking (SPT) analysis (Fig.…”

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

confidence: 75%

“…Because SPT determinations are discontinuous, budding and reinsertion into the membrane can be interpreted as increased lateral diffusion. Dynamin activity is associated with caveolae pinching off the PM (26,27,30,31). To determine the impact of budding off and on the plasma membrane, we sought to inhibit dynamin.…”

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

confidence: 99%

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

confidence: 75%

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

confidence: 99%

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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“…Moreover, the differing molecular composition of cavin complexes across cell types [e.g., cardiomyocytes express all cavin isoforms except for cavin 3 (22,48)] suggests that additional proteins contribute to caveolae formation and confer tissue-specific functions (49). For instance, EHD2, a member of the EHD family of endosomal recycling proteins (50) recently reported to regulate cardiac membrane protein targeting (51,52), has been shown to interact with cavin 1 and control the stability and turnover of caveolae (53). Our data contribute to the expanding list of caveolae regulators and establish FGF13 as a noncavin protein in heart that regulates caveolae density by tuning the balance of cavin 1 between membrane and cytosol.…”

Section: Discussionmentioning

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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“…[31] EHD2 is an ATPase, present at the neck of caveolae. [50][51][52] EHD2 is not required for caveolae formation but stabilizes the caveolae at the plasma membrane. EHD2 depletion results in increased Cav mobility and caveolae endocytosis.…”

Section: The Caveolae Structurementioning

confidence: 99%