An Overview of the Molecular Mechanism of Autophagy
Autophagy is a highly conserved cellular degradation process in which portions of cytosol and organelles are sequestered into a double-membrane vesicle, an autophagosome, and delivered into a degradative organelle, the vacuole/lysosome, for breakdown and eventual recycling of the resulting macromolecules. This process relieves the cell from various stress conditions. Autophagy plays a critical role during cellular development and differentiation, functions in tumor suppression, and may be linked to life span extension. Autophagy also has diverse roles in innate and adaptive immunity, such as resistance to pathogen invasion. Substantial progress has been made in the identification of many autophagy-related (ATG) genes that are essential to drive this cellular process, including both selective and nonselective types of autophagy. Identification of the ATG genes in yeast, and the finding of orthologs in other organisms, reveals the conservation of the autophagic machinery in all eukaryotes. Here, we summarize our current knowledge about the machinery and molecular mechanism of autophagy.
KeywordsAutophagosome Formation Autophagic Activity Selective Autophagy Active Cysteine Atg16 Complex
This work was supported by National Institutes of Health Public Health Service grant GM53396 to D.J.K.
- Berg TO, Fengsrud M, Stromhaug PE, Berg T, Seglen PO (1998) Isolation and characterization of rat liver amphisomes. Evidence for fusion of autophagosomes with both early and late endosomes. J Biol Chem 273:21883–21892Google Scholar
- Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, Ohsumi M, Takao T, Noda T, Ohsumi Y (2000) The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. J Cell Biol 151:263–276PubMedGoogle Scholar
- Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E, Tanaka K (2007b) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131:1149–1163PubMedGoogle Scholar
- Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM, Mills GB (2007) The energy sensing LKB1–AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9:218–224PubMedGoogle Scholar
- Nice DC, Sato TK, Stromhaug PE, Emr SD, Klionsky DJ (2002) Cooperative binding of the cytoplasm to vacuole targeting pathway proteins, Cvt13 and Cvt20, to phosphatidylinositol 3-phosphate at the pre-autophagosomal structure is required for selective autophagy. J Biol Chem 277:30198–30207PubMedGoogle Scholar
- Panaretou C, Domin J, Cockcroft S, Waterfield MD (1997) Characterization of p150, an adaptor protein for the human phosphatidylinositol (PtdIns) 3-kinase. Substrate presentation by phosphatidylinositol transfer protein to the p150·Ptdins 3-kinase complex. J Biol Chem 272:2477–2485PubMedGoogle Scholar
- Yorimitsu T, Klionsky DJ (2005b) Autophagy: molecular machinery for self-eating. Cell Death Differ 12 Suppl 2:1542–1552Google Scholar
- Yorimitsu T, He C, Wang K, Klionsky DJ (2009) Tap42-associated protein phosphatase type 2A negatively regulates induction of autophagy. Autophagy 5:in pressGoogle Scholar