Autophagy Signaling

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• Reviews
• Pathway Key
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Pathway Description:

Autophagy is a catabolic process that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents. Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological processes such as development, differentiation, neurodegenerative diseases, 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. The components of the molecular machinery responsible for autophagy are products of the autophagy-related (Atg) genes. These genes control a number of aspects of the autophagic process including induction by Beclin-1 (Atg6) and autophagosomal vesicle formation through Atg12-Atg5 and LC3 (Atg8). Autophagy and apoptosis are connected both positively and negatively, and extensive crosstalk exists between the two. During nutrient deficiency, autophagy functions as a pro-survival mechanism; however, excessive autophagy leads to autophagic cell death, a process morphologically distinct from apoptosis. Several pro-apoptotic signals, such as TNF, TRAIL and FADD, also induce autophagy and pro-survival signaling through the PI3K/Akt/mTOR pathway suppresses autophagy. Additionally, Bcl-2 binds Beclin-1 to inhibit Beclin-1-dependent autophagy, thereby functioning both as a pro-survival and as an anti-autophagic regulator.

Selected Reviews:

• Gustafsson AB, Gottlieb RA (2008) Recycle or die: the role of autophagy in cardioprotection. J. Mol. Cell. Cardiol. 44(4), 654–61.
• Høyer-Hansen M, Jäättelä M (2008) Autophagy: an emerging target for cancer therapy. Autophagy 4(5), 574–80.
• Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1), 27–42.
• Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451(7182), 1069–75.
• Rajawat YS, Bossis I (2008) Autophagy in aging and in neurodegenerative disorders. Hormones (Athens) 7(1), 46–61.