Autophagy

Macroautophagy, hereafter autophagy, is an evolutionarily conserved degradation process that targets long-lived proteins, organelles, and other cytoplasmic components for degradation via the lysosomal pathway. The autophagy pathway is complementary to the action of the ubiquitin-proteasome pathway which typically degrades short-lived proteins. Activation of the autophagy pathway is required for multiple cellular roles, including survival during starvation, the clearance of intracellular components, development, and immunity.

The initiation of the autophagy pathway in mammalian cells is regulated by a protein complex consisting of unc-52-like kinase (ULK), Atg 13, and FIP200. This complex is regulated by the mammalian target of rapamycin complex 1 (mTORC1), which negatively regulates the activity of ULK1 and ULK2 via phosphorylation. Inactivation of the mTORC1 complex, for example by starvation or rapamycin, results in the phosphorylation and activation of Atg13 and FIP200 and the subsequent elongation of the isolation membrane (also called the phagophore). The further nucleation and assembly of the isolation membrane is dependent on the actions of class III phosphatidylinositol complex consisting of hVps34, hVps15, Beclin 1, and Atg14L. Following the initation phase, the membrane elongates around the degradation targets and seals itself, forming the autophagosome, a process requiring the Atg12, Atg5, Atg16L complex and LC3 (which is cleaved and conjugated to phosphatidylethanolamine in the process forming LC3-II). LC3-II will remain associated with the autophagosome until lysosomal fusion and is commonly used to monitor autophagy. Following autophagosome-lysosome fusion, the components of the lysosome, including cathepsins, lipases, and glycolytic enzymes, degrade the contents of the autolysosome. Lysosomal permeases allow for the release of the degradation breakdown products such as amino acids, carbohydrates, lipds, and nucleosides back into the cytosolic pool where they can be utilized for further metabolic processes.

Decreases in autophagy occur during aging and may be associated with many age-related pathologies such as dementia and cancer. In the absence of stress, autophagy serves a house-keeping function, removing damaged organelles and cellular components preventing cytotoxic effects. For example, the removal of depolarized mitochondria by autophagy is critical for protecting cells from oxidative damage. Decreases and defects in autophagy have been implicated in multiple diseases, for example Huntington′s, Alzheimer′s, and Parkinson′s. In terms of cancer development, autophagy seems to play multiple roles. Decreased or absent expression of certain autophagy proteins, such as Beclin-1 and Bif-1, increases tumor susceptibility in mice while the overexpression of these proteins can repress cancer cell growth. However, autophagy is critical for the survival of cancer cells within the nutrient poor and hypoxic core of solid tumors.

1. Rabinowitz, J.D. and White, E., Autophagy and Metabolism. Science, 330, 1344-1348 (2010)
2. Mehrpour, M. et al., Overview of macroautophagy regulation in mammalian cells. Cell Res., 20, 748-762 (2010)
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