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autophagy | GeneGlobe



Pathway Description

Autophagy is a general term for the basic catabolic mechanism that involves cellular degradation of unnecessary or dysfunctional cellular components through the actions of lysosomes. There are three types of autophagy; macroautophagy, microautophagy, and chaperone-mediated autophagy. The term "autophagy" usually indicates macroautophagy unless otherwise specified.

Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological as well as pathological processes such as development, differentiation, neurodegenerative diseases, stress, infection, and cancer.

The kinase mTOR is a critical regulator of autophagy induction, with activated mTOR (Akt and MAPK signaling) suppressing autophagy, and negative regulation of mTOR (AMPK and p53 signaling) promoting it.

In the first step of autophagosome formation, cytoplasmic constituents, including organelles, are sequestered by a unique membrane called the phagophore or isolation membrane, which is a very flat organelle resembling a Golgi cisterna. Multiple ATG proteins govern autophagosome formation. In response to inactivation of mTOR, the ULK1 complex is activated and translocates in proximity of the endoplasmic reticulum (ER). Thereafter, the ULK1 complex regulates the class III PI3K complex. ATG9L, a multimembrane spanning protein, is also involved in an early stage of autophagosome formation by supplying part of the membranes necessary for formation and expansion.

ATG12 was the first ubiquitin-like Atg protein to be identified, which can be activated by ATG7 and ATG10. Then it is conjugated to ATG5 and promotes the formation of the autophagy precursor. The PI3P-binding WIPI proteins, as well as the ATG12-ATG5-ATG16L1 complex and the LC3-phosphatidylethanolamine (PE) conjugate, play important roles in the elongation and closure of the isolation membrane. LC3 (ATG8) is cleaved at its C-terminus by ATG4 protease to generate the cytosolic LC3-I. LC3-I is conjugated to phosphatidylethanolamine (PE) in a ubiquitin-like reaction that requires ATG7 and ATG3. The lipidated form of LC3, known as LC3-II, is attached to the autophagosome membrane. It is ultimately removed from the outer membrane, which is followed by fusion of the autophagosome with a late endosome/lysosome. LAMP proteins, but especially LAMP-2, are important regulators in successful maturation of both autophagosomes and phagosomes. LAMP-1 and LAMP-2 are estimated to contribute to about half of all proteins of the lysosome membrane. The HOPS complex promotes autophagosome-lysosome fusion through interaction with STX17.

In the autophagolysosome, the cytoplasmic materials are degraded by resident hydrolases and the resulting amino acids and other cellular constituents are then re-used by the cell. When present in high levels they also reactivate mTOR and subsequently suppress autophagy.