Autophagosome formation and molecular mechanism of autophagy.
Autophagy (macroautophagy), or the degradation of large numbers of cytoplasmic components, is induced by extracellular and intracellular signals, including oxidative stress, ceramide, and endoplasmic reticulum stress. This dynamic process involves membrane formation and fusion, including autophagosome formation, autophagosome-lysosome fusion, and the degradation of intra-autophagosomal contents by lysosomal hydrolases. Autophagy is associated with tumorigenesis, neurodegenerative diseases, cardiomyopathy, Crohn's disease, fatty liver, type II diabetes, defense against intracellular pathogens, antigen presentation, and longevity. Among the proteins and multimolecular complexes that contribute to autophagosome formation are the PI(3)-binding proteins, the PI3-phosphatases, the Rab proteins, the Atg1/ULK1 protein-kinase complex, the Atg9•Atg2-Atg18 complex, the Vps34-Atg6/beclin1 class III PI3-kinase complex, and the Atg12 and Atg8/LC3 conjugation systems. Two ubiquitin-like modifications, the Atg12 and LC3 conjugations, are essential for membrane elongation and autophagosome formation. Recent findings have revealed that processes of selective autophagy, including pexophagy, mitophagy, ERphagy (reticulophagy), and the p62-dependent degradation of ubiquitin-positive aggregates, are physiologically important in various disease states, whereas "classical" autophagy is considered nonselective degradation. Processes of selective autophagy require specific Atg proteins in addition to the "core" Atg complexes. Finally, methods to monitor autophagic activity in mammalian cells are described.
Tanida
Isei
I
Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Shinjyuku, Japan. tanida@nih.go.jp
D000818:Animals; D001343:Autophagy; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D046912:Multiprotein Complexes / Q000378:metabolism; D018384:Oxidative Stress; D010588:Phagosomes / Q000378:metabolism* / Q000473:pathology
D046912:Multiprotein Complexes