Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4

Scherz-Shouval, R. et al., EMBO J. 26, 1749–1760 (2007)

Abstract

Autophagy is a major intracellular degradation and recycling pathway for long-lived proteins and organelles.  During autophagy, a cup-shaped structure engulfs cytosolic components and closes to form an autophagosome.  The formation of autophagosome is dependent upon many autophagy-related genes (ATGs).  The reversible conjugation of the Atg8 family proteins, including the mammalian homologues GATE-16, GABARAP and LC3, to the autophagosomal membrane is a hallmark event in the autophagic process.  Cysteine protease Atg4 cleaves Atg8 proteins near their C-terminus and this cleavage allows the conjugation of Atg8 to membrane phospholipids, phosphatidylethanolamine (PE).  Atg4 can also cleave Atg8-PE and release Atg8 from the autophagosomal membrane.  Following the initial cleavage of Atg8 proteins, Atg4 becomes inactive so as to ensure the conjugation of Atg8 to autophagosomal membrane.  Hence, Atg4 proteins act both as conjugating and deconjugating enzymes and their activity must be tightly regulated during autophagy.  However, the molecular mechanism regulating Atg4 activity remains largely unknown.  The involvement of reactive oxygen species (ROS) as signaling molecules has been suggested in many stress responses.  In this study, the authors determined that nutrient deprivation stimulated the accumulation of ROS within cells.  Antioxidants suppressed starvation-induced autophagy, suggesting that ROS were essential for autophagy.  Interestingly, the delipidation activity of Atg4 was attenuated under nutrient starvation in a redox-dependent manner.  Mutations in Cys81 and Cys78 significantly reduced the redox sensitivities of HsAtg4A and HsAtg4B, respectively. Taken together, these results first describe a role for ROS as signaling molecules in starvation-induced autophagy and identify Atg4 as a target for redox regulation.

References

1.      Liu, Z. and Lenardo, M. J. Reactive oxygen species regulate autophagy through redox-sensitive proteases. Dev. Cell 12, 484-485 (2007).

2.      Scherz-Shouval, R. et al. The COOH terminus of GATE-16, an intra-Golgi transport modulator, is cleaved by the human cysteine protease HsApg4A. J. Biol. Chem. 278, 14053–14058 (2003).