Cholesterol and ORP1L-mediated ER contact sites control autophagosome transport and fusion with the endocytic pathway.
Cholesterol and ORP1L-mediated ER contact sites control autophagosome transport and fusion with the endocytic pathway.
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DOI：
10.1038/ncomms11808
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发表时间：
2016-06-10
影响因子：
16.6
通讯作者：
Neefjes J
中科院分区：
文献类型：
--
作者：
Wijdeven RH;Janssen H;Nahidiazar L;Janssen L;Jalink K;Berlin I;Neefjes J
自噬是介导细胞溶质物质被溶酶体降解的主要稳态途径。自噬体的成熟需要它们向细胞的核周区域运输，这两个过程的关键因素仍然知之甚少。在这里，我们表明，运输和定位的晚期自噬体依赖于胆固醇的方式的胆固醇敏感Rab 7效应ORP 1 L。ORP 1 L定位于晚期自噬体，并在低胆固醇条件下接触ER蛋白VAP-A，形成ER-自噬体接触位点，其阻止Rab 7-RILP-动力蛋白复合物的负端转运。ORP 1 L介导的接触位点也抑制PLEKHM 1定位于Rab 7。然后，PLEKHM 1与RILP一起招募同型融合和空泡蛋白分选（HOPS）复合物，用于自噬体与晚期内体和溶酶体的融合。因此，ORP 1 L，通过其配体的脂质和自噬空泡和ER之间的接触的形成，管理在自噬的最后步骤，导致溶酶体降解的胞质物质。 自噬需要将自噬体运输到核周区域。在这里，作者表明ORP 1 L定位于自噬体并介导ER接触位点的形成，当胆固醇水平低时，ER接触位点阻止自噬体转运和与内吞囊泡融合。
Autophagy is the main homeostatic pathway guiding cytosolic materials for degradation by the lysosome. Maturation of autophagosomes requires their transport towards the perinuclear region of the cell, with key factors underlying both processes still poorly understood. Here we show that transport and positioning of late autophagosomes depends on cholesterol by way of the cholesterol-sensing Rab7 effector ORP1L. ORP1L localizes to late autophagosomes and—under low-cholesterol conditions—contacts the ER protein VAP-A, forming ER-autophagosome contact sites, which prevent minus-end transport by the Rab7–RILP–dynein complex. ORP1L-mediated contact sites also inhibit localization of PLEKHM1 to Rab7. PLEKHM1, together with RILP, then recruits the homotypic fusion and vacuole protein-sorting (HOPS) complex for fusion of autophagosomes with late endosomes and lysosomes. Thus, ORP1L, via its liganding by lipids and the formation of contacts between autophagic vacuoles and the ER, governs the last steps in autophagy that lead to the lysosomal degradation of cytosolic material. Autophagy requires transport of autophagosomes to the perinuclear region. Here, the authors show that ORP1L localizes to autophagosomes and mediates formation of ER contact sites that prevent autophagosome transport and fusion with endocytic vesicles when cholesterol levels are low.