PDZD8-mediated lipid transfer at contacts between the ER and late endosomes/lysosomes is required for neurite outgrowth
PDZD8-mediated lipid transfer at contacts between the ER and late endosomes/lysosomes is required for neurite outgrowth
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PDZD8 介导的 ER-LE/lys 接触处的脂质转移是 LE/lys 定位和神经突生长所必需的
DOI：
10.1242/jcs.255026
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发表时间：
2022-03-01
影响因子：
4
通讯作者：
Ji, Wei-Ke
中科院分区：
文献类型：
--
作者：
Gao, Yuan;Xiong, Juan;Ji, Wei-Ke
内质网（ER）和晚期内体/溶酶体（LE/lys）之间的膜接触位点（MCSs）正在成为多种细胞事件的关键枢纽，其程度的变化与严重的神经系统疾病有关。虽然最近的研究表明，含有synaptotagin样线粒体-脂质结合（SMP）结构域的蛋白PDZD8可能介导ER-LE/lys MCSs的形成，但PDZD8的细胞功能在很大程度上仍是未知的。在这里，我们试图研究PDZD8的脂质转移活性以及它的细胞功能在多大程度上依赖于它的脂质转移活性。根据最近的研究，我们证明PDZD8是一种突起蛋白（ZFYVE27）相互作用蛋白，PDZD8在ER-LE/lys MCSs中起系链作用。此外，我们发现PDZD8的SMP结构域在体内和体外都能结合甘油磷脂和神经酰胺，并且SMP结构域可以在体外膜间运输脂质。在功能上，PDZD8是LE/lys定位和神经突生长所必需的，这取决于SMP结构域的脂质转移活性。本文以第一人称采访了该论文的第一作者。
Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and late endosomes/lysosomes (LE/lys) are emerging as critical hubs for diverse cellular events, and changes in their extents are linked to severe neurological diseases. While recent studies show that the synaptotagmin-like mitochondrial-lipid-binding (SMP) domain-containing protein PDZD8 may mediate the formation of ER-LE/lys MCSs, the cellular functions of PDZD8 remain largely elusive. Here, we attempt to investigate the lipid transfer activities of PDZD8 and the extent to which its cellular functions depend on its lipid transfer activities. In accordance with recent studies, we demonstrate that PDZD8 is a protrudin (ZFYVE27)-interacting protein and that PDZD8 acts as a tether at ER-LE/lys MCSs. Furthermore, we discover that the SMP domain of PDZD8 binds glycerophospholipids and ceramides both in vivo and in vitro, and that the SMP domain can transport lipids between membranes in vitro. Functionally, PDZD8 is required for LE/lys positioning and neurite outgrowth, which is dependent on the lipid transfer activity of the SMP domain.This article has an associated First Person interview with the first author of the paper.