Autophagosomes form at ER-mitochondria contact sites
Autophagosomes form at ER-mitochondria contact sites
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DOI：
10.1038/nature11910
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发表时间：
2013-03-21
期刊：
影响因子：
64.8
通讯作者：
Yoshimori, Tamotsu
中科院分区：
文献类型：
--
作者：
Hamasaki, Maho;Furuta, Nobumichi;Yoshimori, Tamotsu
自噬是一种受到严格调控的细胞内大量降解/再循环系统，在细胞内稳态中发挥重要作用（1）。自噬是由隔离膜启动的，隔离膜在吞噬部分细胞质和细胞器时形成并伸长。最终，隔离膜形成双膜结合的自噬体，并与溶酶体融合以降解其内容物。自噬的生理作用自发现以来就已确定，但自噬体膜的起源仍不清楚。目前，关于膜起源的细胞器-内质网（ER）、线粒体和质膜（1，2）存在很大争议。在这里，我们表明，自噬体的形式在ER-线粒体接触网站在哺乳动物细胞。成像数据显示，前自噬体/自噬体标记物ATG 14（也称为ATG 14 L）在饥饿后重新定位于ER-线粒体接触位点，并且自噬体形成标记物ATG 5也定位于该位点，直到形成完成。亚细胞分级分离显示，在饥饿条件下，ATG 14共分级分离在与ESTA相关的ER膜（3-5）级分中。ER-线粒体接触位点的破坏阻止了ATG 14斑点的形成。ER驻留SNARE蛋白syntaxin 17（STX 17）结合ATG 14并将其募集到ER-线粒体接触位点。这些结果通过证明ER-线粒体接触位点在自噬体形成中是重要的，为细胞器生物发生提供了新的见解。
Autophagy is a tightly regulated intracellular bulk degradation/recycling system that has fundamental roles in cellular homeostasis(1). Autophagy is initiated by isolation membranes, which form and elongate as they engulf portions of the cytoplasm and organelles. Eventually isolation membranes dose to form double membrane-bound autophagosomes and fuse with lysosomes to degrade their contents. The physiological role of autophagy has been determined since its discovery, but the origin of autophagosomal membranes has remained unclear. At present, there is much controversy about the organelle from which the membranes originate-the endoplasmic reticulum (ER), mitochondria and plasma membrane(1,2). Here we show that autophagosomes form at the ER-mitochondria contact site in mammalian cells. Imaging data reveal that the pre-autophagosome/autophagosome marker ATG14 (also known as ATG14L) relocalizes to the ER-mitochondria contact site after starvation, and the autophagosome-formation marker ATG5 also localizes at the site until formation is complete. Subcellular fractionation showed that ATG14 co-fractionates in the mitochondria-associated ER membrane(3-5) fraction under starvation conditions. Disruption of the ER-mitochondria contact site prevents the formation of ATG14 puncta. The ER-resident SNARE protein syntaxin 17 (STX17) binds ATG14 and recruits it to the ER-mitochondria contact site. These results provide new insight into organelle biogenesis by demonstrating that the ER-mitochondria contact site is important in autophagosome formation.