ER-plasma membrane (PM) contacts are proposed to be held together by distinct families of tethering proteins, which in yeast include the VAP homologues Scs2/22, the extended-synaptotagmin homologues Tcb1/2/3, and the TMEM16 homologue Ist2. It is unclear whether these tethers act redundantly or whether individual tethers have specific functions at contacts. Here, we show that Ist2 directly recruits the phosphatidylserine (PS) transport proteins and ORP family members Osh6 and Osh7 to ER–PM contacts through a binding site located in Ist2’s disordered C-terminal tethering region. This interaction is required for phosphatidylethanolamine (PE) production by the PS decarboxylase Psd2, whereby PS transported from the ER to the PM by Osh6/7 is endocytosed to the site of Psd2 in endosomes/Golgi/vacuoles. This role for Ist2 and Osh6/7 in nonvesicular PS transport is specific, as other tethers/transport proteins do not compensate. Thus, we identify a molecular link between the ORP and TMEM16 families and a role for endocytosis of PS in PE synthesis.

中文翻译：

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Ist2 将脂质转运蛋白 Osh6/7 招募到 ER-PM 接触点以维持磷脂代谢

ER-质膜 (PM) 接触被认为是由不同的束缚蛋白家族连接在一起，在酵母中，这些蛋白家族包括 VAP 同源物 Scs2/22、延伸突触结合蛋白同源物 Tcb1/2/3 和 TMEM16 同源物 Ist2。目前还不清楚这些系绳是否有多余的作用，或者单个系绳是否在接触处具有特定的功能。在这里，我们发现 Ist2 通过位于 Ist2 无序 C 末端束缚区域的结合位点直接将磷脂酰丝氨酸 (PS) 转运蛋白和 ORP 家族成员 Osh6 和 Osh7 招募到 ER-PM 接触点。这种相互作用是 PS 脱羧酶 Psd2 产生磷脂酰乙醇胺 (PE) 所必需的，由此 Osh6/7 从 ER 转运至 PM 的 PS 被内吞至核内体/高尔基体/液泡中的 Psd2 位点。Ist2 和 Osh6/7 在非囊泡 PS 转运中的作用是特定的，因为其他系链/转运蛋白无法补偿。因此，我们确定了 ORP 和 TMEM16 家族之间的分子联系以及 PS 内吞作用在 PE 合成中的作用。