Autophagy Signaling Pathway

Autophagy Pathway Background

Autophagy,the 2016 Nobel Prize in Physiology or Medicine, is a dynamic cellular recycling system that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents, abnormal protein aggregates, and excess or damaged organelles. The critical regulator of autophagy induction is mTOR kinase, that activated mTOR (Akt and MAPK signaling) suppressing autophagy, and negative regulation of mTOR (AMPK and p53 signaling) promoting it. The ULK which play a similar role as the yeast Atg1, act downstream of the mTOR complex. ULK forms a large complex with Atg13 and the scaffold protein FIP200. Class III PI3K complex, containing hVps34, Beclin-1 (a mammalian homolog of yeast Atg6), p150 (a mammalian homolog of yeast Vps15), and Atg14-like protein (Atg14L or Barkor) or ultraviolet irradiation resistance-associated gene (UVRAG), is required for the induction of autophagy. Rubicon inhibits PI3K class III lipid kinase activity and opposes the action of Atg14L, an enhancer of PI3K class III activity. The Atg genes control the autophagosome formation through Atg12-Atg5 and LC3-II (Atg8-II) complexes. Atg12 is conjugated to Atg5 in a ubiquitin-like reaction that requires Atg7 and Atg10 (E1 and E2-like enzymes, respectively). The Atg12–Atg5 conjugate then interacts noncovalently with Atg16 to form a large complex. The second complex, 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 (E1 and E2-like enzymes, respectively). The lipidated form of LC3, known as LC3-II, is attached to the autophagosome membrane. Autophagy and apoptosis are connected both positively and negatively, and extensive crosstalk exists between the two processes. During nutrient deficiency, autophagy functions as a pro-survival mechanism; however, excessive autophagy may lead to cell death, a process morphologically distinct from apoptosis. Several pro-apoptotic signals, such as TNF, TRAIL, and FADD, also induce autophagy. Additionally, Bcl-2 inhibits Beclin-1-dependent autophagy, thereby functioning both as a pro-survival and as an anti-autophagic regulator.

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