Saheki Yasunori, Bian Xin, Schauder Curtis M, Sawaki Yujin, Surma Michal A, Klose Christian, Pincet Frederic, Reinisch Karin M, De Camilli Pietro
Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Nat Cell Biol. 2016 May;18(5):504-15. doi: 10.1038/ncb3339. Epub 2016 Apr 11.
Acute metabolic changes in plasma membrane (PM) lipids, such as those mediating signalling reactions, are rapidly compensated by homeostatic responses whose molecular basis is poorly understood. Here we show that the extended synaptotagmins (E-Syts), endoplasmic reticulum (ER) proteins that function as PtdIns(4,5)P2- and Ca(2+)-regulated tethers to the PM, participate in these responses. E-Syts transfer glycerolipids between bilayers in vitro, and this transfer requires Ca(2+) and their lipid-harbouring SMP domain. Genome-edited cells lacking E-Syts do not exhibit abnormalities in the major glycerolipids at rest, but exhibit enhanced and sustained accumulation of PM diacylglycerol following PtdIns(4,5)P2 hydrolysis by PLC activation, which can be rescued by expression of E-Syt1, but not by mutant E-Syt1 lacking the SMP domain. The formation of E-Syt-dependent ER-PM tethers in response to stimuli that cleave PtdIns(4,5)P2 and elevate Ca(2+) may help reverse accumulation of diacylglycerol in the PM by transferring it to the ER for metabolic recycling.
质膜（PM）脂质的急性代谢变化，例如介导信号反应的那些变化，会迅速被稳态反应所补偿，而其分子基础却知之甚少。在这里，我们表明，延伸突触结合蛋白（E-Syts），即作为受磷脂酰肌醇-4,5-二磷酸（PtdIns(4,5)P2）和钙离子（Ca(2+)）调节的内质网（ER）与质膜连接蛋白发挥作用的内质网蛋白，参与了这些反应。E-Syts在体外双层膜之间转移甘油脂质，这种转移需要钙离子和它们带有脂质的SMP结构域。缺乏E-Syts的基因编辑细胞在静息状态下主要甘油脂质没有异常，但在通过磷脂酶C（PLC）激活水解PtdIns(4,5)P2后，质膜二酰甘油会出现增强且持续的积累，这种积累可以通过表达E-Syt1来挽救，但不能通过缺乏SMP结构域的突变型E-Syt1来挽救。响应于切割PtdIns(4,5)P2并升高钙离子的刺激而形成的依赖E-Syt的内质网-质膜连接可能通过将二酰甘油转移到内质网进行代谢循环，有助于逆转其在质膜中的积累。
