Osh6 and Osh7 are lipid transfer proteins (LTPs) that move phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM). High PS levels at the PM are key for many cellular functions. Intriguingly, Osh6 and Osh7 localize to ER–PM contact sites, although they lack membrane-targeting motifs, in contrast to multidomain LTPs that both bridge membranes and convey lipids. We show that Osh6 localization to contact sites depends on its interaction with the cytosolic tail of the ER–PM tether Ist2, a homolog of TMEM16 proteins. We identify a motif in the Ist2 tail, conserved in yeasts, as the Osh6-binding region, and we map an Ist2-binding surface on Osh6. Mutations in the Ist2 tail phenocopy osh6 osh7 deletion: they decrease cellular PS levels and block PS transport to the PM. Our study unveils an unexpected partnership between a TMEM16-like protein and a soluble LTP, which together mediate lipid transport at contact sites.

This article has an associated First Person interview with the first author of the paper.

Osh6 和 Osh7 是脂质转移蛋白 (LTP)，可将磷脂酰丝氨酸 (PS) 从内质网 (ER) 转移到质膜 (PM)。PM 的高 PS 水平是许多细胞功能的关键。有趣的是，Osh6 和 Osh7 定位于 ER-PM 接触位点，尽管它们缺乏膜靶向基序，与桥接膜和输送脂质的多域 LTP 形成对比。我们表明 Osh6 定位到接触位点取决于它与 ER-PM 系链 Ist2 的胞质尾部的相互作用，这是 TMEM16 蛋白的同源物。我们将在酵母中保守的 Ist2 尾部中的一个基序识别为 Osh6 结合区域，并且我们在 Osh6 上绘制了一个 Ist2 结合表面。Ist2 尾部表型osh6 osh7中的突变删除：它们降低细胞 PS 水平并阻止 PS 转运至 PM。我们的研究揭示了 TMEM16 样蛋白和可溶性 LTP 之间的一种意想不到的伙伴关系，它们共同介导接触部位的脂质转运。

本文与论文的第一作者进行了相关的第一人称采访。