Activation of the lifespan regulator p66Shc through reversible disulfide bond formation.
Cell fate and organismal lifespan are controlled by a complex signaling network whose dysfunction can cause a variety of aging-related diseases. An important protection against these failures is cellular apoptosis, which can be induced by p66(Shc) in response to cellular stress. The precise mechanisms of p66(Shc) action and regulation and the function of the p66(Shc)-specific N terminus remain to be identified. Here, we show that the p66(Shc) N terminus forms a redox module responsible for apoptosis initiation, and that this module can be activated through reversible tetramerization by forming two disulfide bonds. Glutathione and thioredoxins can reduce and inactivate p66(Shc), resulting in a thiol-based redox sensor system that initiates apoptosis once cellular protection systems cannot cope anymore with cellular stress.
Gertz
Melanie
M
Departments of Physiological Chemistry and Analytical Chemistry, Ruhr-University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany.
Fischer
Frank
F
Wolters
Dirk
D
Steegborn
Clemens
C
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D003001:Cloning, Molecular; D019281:Dimerization; D004220:Disulfides; D005978:Glutathione / Q000494:pharmacology; D008136:Longevity; D051379:Mice; D008930:Mitochondria, Liver; D010084:Oxidation-Reduction; D051381:Rats; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013879:Thioredoxins / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D004220:Disulfides; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013879:Thioredoxins; D005978:Glutathione