Autophagy Signaling

Macroautophagy, often referred to as autophagy, is a catabolic process that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents, abnormal protein aggregates, and excess or damaged organelles. 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. Three related serine/threonine kinases, UNC-51-like kinase -1, -2, and -3 (ULK1, ULK2, UKL3), which play a similar role as the yeast Atg1, act downstream of the mTOR complex. ULK1 and ULK2 form a large complex with the mammalian homolog of an autophagy-related (Atg) gene product (mAtg13) and the scaffold protein FIP200 (an ortholog of yeast Atg17). 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. The Atg genes control 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. LC3/Atg8 is cleaved at its C-terminus by Atg4 protease to generate the cytosolic LC3-I. LC3-I is conjugated to phosphatidylethanolamine (PE) also 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.

Mitophagy is a selective autophagic process specifically designed for the removal of damaged or unneeded mitochondria from a cell. Upon mitochondrial damage, the proteinPINK, which is continually degraded in the healthy state through the action of PARL, is stabilized and recruits the E3 ligase Parkin to initiate mitophagy. Polyubiquitination of mitochondrial membrane proteins by Parkin results in the recruitment of autophagy adaptor proteins SQSTM1/p62, NBR1, and Ambra1 that bind to LC3 via their LC3-interacting region (LIR). In addition, BNIP3 and BNIP3L/NIX, which also contain LIRs, directly recruit autophagic machinery by a ubiquitin-independent mechanism to induce autophagosome formation in certain cell types.

Selected Reviews:

• Alers S, Löffler AS, Wesselborg S, Stork B (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol. Cell. Biol. 32(1), 2–11.
• Codogno P, Mehrpour M, Proikas-Cezanne T (2012) Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat. Rev. Mol. Cell Biol. 13(1), 7–12.
• Ding WX, Yin XM (2012) Mitophagy: mechanisms, pathophysiological roles, and analysis. Biol. Chem. 393(7), 547–64.
• Feng D, Liu L, Zhu Y, Chen Q (2013) Molecular signaling toward mitophagy and its physiological significance. Exp. Cell Res. 319(12), 1697–705.
• Ding WX, Yin XM (2012) Mitophagy: mechanisms, pathophysiological roles, and analysis. Biol. Chem. 393(7), 547–64.
• Papinski D, Kraft C (2014) Atg1 kinase organizes autophagosome formation by phosphorylating Atg9. Autophagy 10(7), 1338–40.
• Schneider JL, Cuervo AM (2014) Autophagy and human disease: emerging themes. Curr. Opin. Genet. Dev. 26, 16–23.

We would like to thank Prof. Bingren Hu, University of Maryland School of Medicine, Baltimore, MD, for reviewing this diagram.

created September 2007

revised September 2016