Autophagy

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Autophagy

Autophagy is a multifunctional, intracellular process that has an important role in protecting eukaryotic cells and maintaining intracellular homoeostasis. Autophagy is orchestrated by a number of highly conserved AuTophaGy-related genes (ATGs). The ‘core’ autophagic machinery encompasses only those ATGs that are necessary for autophagosome formation in all subtypes and these can be divided into several distinct groups: the unc-51-like kinase 1/2 (ULK1/2) complex, the multi-spanning membrane protein Atg9, the PI3K-III complex and the ubiquitin-like ATG12 and microtubule- associated protein 1 light chain 3 alpha (MAP1LC3A) conjugation systems.

Autophagy is activated in response to a whole host of stimuli including nutrient depletion, hypoxia and activated oncogenes. The majority of pro-autophagic events converge on the serine/threonine protein kinase mTOR (MTOR, mammalian/mechanistic target of rapamycin). Three different types of autophagy are defined: microautophagy (refers to the direct engulfment of cytoplasm by the lysosome), chaperone-mediated autophagy (chaperone-dependent selection of soluble cytosolic proteins for lysosomal  degradation with the direct shuttling of these proteins across the lysosomal membrane) and macroautophagy (the substrates are sequestered within cytosolic double-membrane vesicles termed autophagosomes).

Autophagy is known to protect us against various forms of human disease. In some cases, for example neurodegenerative disease, it is clear that autophagy facilitates the removal of aggregate-prone proteins that lead to Huntington’s and Parkinson’s disease. The role of autophagy in cancer, however, is more complex. There is evidence that autophagy may be oncogenic in some contexts, whereas in others, it clearly contributes to tumour suppression. The hypothesis that autophagy is involved in delaying ageing and extending lifespan is partially supported by three lines of evidence: First, the abundance of autophagy related proteins and autophagic activity decline over ageing. Second, a microarray-based genetic screen for genes that function in the regulation of chronological lifespan in yeast revealed that a number of mutants defective for autophagy are short-lived. Third, autophagy is required for the lifespan-extending effect of genetic and pharmacological manipulations in several organisms.