Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4.
Autophagy is a major catabolic pathway by which eukaryotic cells degrade and recycle macromolecules and organelles. This pathway is activated under environmental stress conditions, during development and in various pathological situations. In this study, we describe the role of reactive oxygen species (ROS) as signaling molecules in starvation-induced autophagy. We show that starvation stimulates formation of ROS, specifically H(2)O(2). These oxidative conditions are essential for autophagy, as treatment with antioxidative agents abolished the formation of autophagosomes and the consequent degradation of proteins. Furthermore, we identify the cysteine protease HsAtg4 as a direct target for oxidation by H(2)O(2), and specify a cysteine residue located near the HsAtg4 catalytic site as a critical for this regulation. Expression of this regulatory mutant prevented the formation of autophagosomes in cells, thus providing a molecular mechanism for redox regulation of the autophagic process.
Scherz-Shouval
Ruth
R
Department of Biological Chemistry, The Weizmann Institute of Science, 76100 Rehovot, Israel.
Shvets
Elena
E
Fass
Ephraim
E
Shorer
Hagai
H
Gil
Lidor
L
Elazar
Zvulun
Z
D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003545:Cysteine / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D005508:Food Deprivation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010802:Phylogeny; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000071183:Autophagy-Related Proteins; D017382:Reactive Oxygen Species; D019869:Phosphatidylinositol 3-Kinases; C474025:ATG4A protein, human; D003546:Cysteine Endopeptidases; D003545:Cysteine