A scheme for the autophagy machinery in mammalian cells. (IMAGE)
Caption
Nutrient deprivation inhibits mTORC1 and activates AMPK, which then dephosphorylates or phosphorylates ULK1 at different sites, leading to the activation of the ULK complex and initiation of the isolation membrane (phagophore) formation. The activated ULK complex recruits the PIK3C3 complex I (PIK3C3-CI) to the initiation sites of the autophagosome, producing the signalling molecule phosphatidylinositol 3-phosphate to promote phagophore membrane biogenesis. Concurrently, two ubiquitin-like conjugation systems, the ATG7–ATG3–ATG8/microtubule-associated protein 1A/1B-light chain 3 (LC3) and ATG12–ATG5–ATG16L1 complexes, conjugate the cytosolic form LC3 (called LC3-I) to phosphatidylethanolamine (PE), forming an autophagosome membrane-anchored LC3-II. By supplying membranes from donor sources, ATG9-mediated cycling systems, which comprise the core proteins ATG9, ATG2, VPS13D and WIPI1/2, facilitate the elongation of phagophore. A mature autophagosome will be formed when the extending phagophore closes, mediated by the ESCRT protein CHAMP2A and the ER transmembrane protein VMP1 and TMEM41B. Autophagosomes eventually fuse with the lysosome mediated by STX17–VAMP7/8–SNAP29 complex and the GTPase RAB7 and complex HOPS, resulting in the degradation of cargos within autolysosomes. Autolysosomes then undergo ALR and lysosome biogenesis mediated by TFEB. ALR, autophagic lysosome reformation; ER, endoplasmic reticulum; ESCRT, endosomal sorting complexes required for transport; TFEB, transcription factor EB.
Credit
By Wen-Xing Ding, Xiaowen Ma, Sydney Kim, Shaogui Wang and Hong-Min Ni.
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Credit must be given to the creator. Only noncommercial uses of the work are permitted.
License
CC BY-NC