Autophagosomes form at ER-mitochondria contact sites

1] Department of Genetics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan [2] Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan [3].
Nature (Impact Factor: 41.46). 03/2013; 495(7441). DOI: 10.1038/nature11910
Source: PubMed


Autophagy is a tightly regulated intracellular bulk degradation/recycling system that has fundamental roles in cellular homeostasis. Autophagy is initiated by isolation membranes, which form and elongate as they engulf portions of the cytoplasm and organelles. Eventually isolation membranes close 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. 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 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.

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    • "Thus, the PS lipids on the extracellular membrane leaflet of the vesicle are in a compartment that is topologically equivalent to the lumenal membrane leaflet of the double-membraned autophagosome-like organelle. The ER is a major membrane source for autophagosomes (Hamasaki et al., 2013) and has lumenal membrane leaflet enriched in PS lipids (Kay et al., 2012). Given that the isolated PS vesicles also contain ER-resident proteins (Figure S2B), it is highly likely that the autophagosome-like organelles , and thereby the released PS vesicles, originated from ER and/or ER-derived replication organelle membranes. "
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