EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription

Torrino, Stéphanie; Shen, Weiwei; Blouin, Cédric M.; Mani, Salma; Lesegno, Christine Viaris de; Bost, Pierre; Grassart, Alexandre; Köster, D; Valades-Cruz, César Augusto; Chambon, Valérie; Johannes, Ludger; Pierobon, Paolo; Soumelis, Vassili; Coirault, Catherine; Vassilopoulos, Stéphane; Lamaze, Christophe

doi:10.1083/jcb.201801122

Cited by 66 publications

(64 citation statements)

References 42 publications

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“…A number of functions have been ascribed to caveolae. A quite recent one is their ability to protect cells against mechanical stress by stretching of the PM, which provides an explanation of the very high density of caveolae in some cell types, such as skeletal muscle, endothelial cells and adipocytes [12,[63][64][65][66][67][68]. Other functions include fatty acid [69] and Ca 2+ [70] transport, as well as endocytosis as discussed below.…”

Section: Caveolaementioning

confidence: 99%

“…In 2012, two groups published that the protein EHD2 (an ATPase) had a stabilizing function at caveolae, preventing pinching off of these structures from the plasma membrane [61,62]. More recently, it was reported that EHD2 is rapidly released from caveolae under mechanical stress, SUMOylated, and translocated to the nucleus, where it regulates the transcription of several genes including those coding for caveolae constituents [63].…”

Section: Caveolaementioning

confidence: 99%

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The role of lipid species in membranes and cancer-related changes

Skotland

Kavaliauskiene

Sandvig

2020

Cancer Metastasis Rev

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Several studies have demonstrated interactions between the two leaflets in membrane bilayers and the importance of specific lipid species for such interaction and membrane function. We here discuss these investigations with a focus on the sphingolipid and cholesterol-rich lipid membrane domains called lipid rafts, including the small flask-shaped invaginations called caveolae, and the importance of such membrane structures in cell biology and cancer. We discuss the possible interactions between the very long-chain sphingolipids in the outer leaflet of the plasma membrane and the phosphatidylserine species PS 18:0/18:1 in the inner leaflet and the importance of cholesterol for such interactions. We challenge the view that lipid rafts contain a large fraction of lipids with two saturated fatty acyl groups and argue that it is important in future studies of membrane models to use asymmetric membrane bilayers with lipid species commonly found in cellular membranes. We also discuss the need for more quantitative lipidomic studies in order to understand membrane function and structure in general, and the importance of lipid rafts in biological systems. Finally, we discuss cancer-related changes in lipid rafts and lipid composition, with a special focus on changes in glycosphingolipids and the possibility of using lipid therapy for cancer treatment.

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Section: Caveolaementioning

confidence: 99%

Section: Caveolaementioning

confidence: 99%

The role of lipid species in membranes and cancer-related changes

Skotland

Kavaliauskiene

Sandvig

2020

Cancer Metastasis Rev

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“…Caveolae are small membrane invaginations of the plasma membrane that are abundantly found 49 in adipocytes, endothelial and muscle cells (Cheng and Nichols, 2016). They have been implicated in the 50 regulation of membrane tension (Sinha et al, 2011;Torrino et al, 2018) Loss of Cav1/Cav3 or Cavin1 results in a complete lack of caveolae from the plasma membrane 61 (Drab et al, 2001;Hill et al, 2008;Liu et al, 2008). Also, Cavin2 knockout (KO) mice show a decreased 62 number of caveolae at the plasma membrane in adipocytes and lung endothelium, but not in 63 cardiomyocytes or heart endothelium, suggesting a cell-type specific function (Hansen et al, 2013).…”

Section: Introduction 48mentioning

confidence: 99%

EHD2-mediated restriction of caveolar dynamics regulates cellular lipid uptake

Matthäus

Lahmann

Kunz

et al. 2019

Preprint

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26Eps15-homology domain containing protein 2 (EHD2) is a dynamin-related ATPase located at the neck of 27 caveolae, but its physiological function has remained unclear. Here, we found that global genetic ablation 28 of EHD2 in mice led to increased fat accumulation. This organismic phenotype was paralleled at the 29 cellular level by increased lipid uptake via a caveolae-, dynamin-and CD36-dependent pathway, an 30 elevated number of detached caveolae and higher caveolar mobility. Furthermore, EHD2 expression itself 31 was down-regulated in the visceral fat of two obese mouse models and obese patients. Our data suggest 32 that EHD2 controls a cell-autonomous, caveolae-dependent lipid uptake pathway and suggest that low 33 EHD2 expression levels are linked to obesity. 34 35 36 Keywords: EHD2, caveolae, fatty acid uptake, lipid metabolism, obesity 37 38 occurrence of compensatory mechanisms. First, we looked for changes of adiponectin, leptin and insulin 126 plasma levels but did not detect any significant difference in mice lacking EHD2 compared to EHD2 del/+ 127 mice (Fig. S3). Free fatty acid concentration in blood plasma was slightly reduced in EHD2 del/del 128 suggesting a possible increase in fatty acid uptake (Fig. S3). Furthermore, we observed a down-regulation 129 of genes involved in de novo lipogenesis in isolated WAT obtained EHD2 del/del vs. EHD2 del/+ mice or in 130 primary adipocyte cell cultures ( Fig. S5B-D) suggesting that downregulation of lipogenesis is an active 131 mechanism that partially compensates for the increased lipid accumulation. 132 133 134

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“…During this process, the Cav/cavin1 interaction is weakened and cavin1 is released into the cytosol, while free Cavs increase at the plasma membrane and EHD2 enters the nucleus. 54,55 When returned to isoosmotic conditions, caveolae reassemble at the cell surface.…”

Section: Syt11 Positively Regulates Caveolar Response Upon Hypoosmomentioning

confidence: 99%

Synaptotagmin‐11 regulates the functions of caveolae and responds to mechanical stimuli in astrocytes

et al. 2019

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Abbreviations: Cav, caveolin; EHD2, EH domain-containing protein 2; Flot-1, flotillin-1; LacCer, BODIPY FL C5-Lactosylceramide; Syt11, synaptotagmin-11; TfR, transferrin receptor. AbstractCaveolae play crucial roles in intracellular membrane trafficking and mechanosensation. In this study, we report that synaptotagmin-11 (Syt11), a synaptotagmin isoform associated with Parkinson's disease and schizophrenia, regulates both caveolaemediated endocytosis and the caveolar response to mechanical stimuli in astrocytes.Syt11-knockout (KO) accelerated caveolae-mediated endocytosis. Interestingly, the caveolar structures on the cell surface were markedly fewer in the absence of Syt11.Caveolar disassembly in response to hypoosmotic stimuli and astrocyte swelling were both impaired in Syt11-KO astrocytes. Live imaging revealed that Syt11 left caveolar structures before cavin1 during hypoosmotic stress and returned earlier than cavin1 after isoosmotic recovery. Chronic hypoosmotic stress led to proteasomemediated Syt11 degradation. In addition, Syt11-KO increased the turnover of cavin1 and EH domain-containing protein 2 (EHD2), accompanied by compromised membrane integrity, suggesting a mechanoprotective role of Syt11. Direct interactions between Syt11 and cavin1 and EHD2, but not caveolin-1, are found. Altogether, we propose that Syt11 stabilizes caveolar structures on the cell surface of astrocytes and regulates caveolar functions under physiological and pathological conditions through cavin1 and EHD2. K E Y W O R D Sastrocyte swelling, endocytosis, hypoosmotic stress, mechanoprotection 2610 | YAN et Al.

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EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription

Cited by 66 publications

References 42 publications

The role of lipid species in membranes and cancer-related changes

The role of lipid species in membranes and cancer-related changes

EHD2-mediated restriction of caveolar dynamics regulates cellular lipid uptake

Synaptotagmin‐11 regulates the functions of caveolae and responds to mechanical stimuli in astrocytes

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