Identification of Peroxiredoxin 1 as a novel interaction partner for the lifespan regulator protein p66Shc.
Damage caused by reactive oxygen species (ROS) contributes to many aging processes and accompanying diseases. ROS are toxic side products of cellular respiration, but also function as signal, e.g. in the mitochondrial apoptosis pathway. The protein p66Shc, which has been implicated in life-span regulation and aging-related diseases, is a central player in stress-induced apoptosis and the associated ROS burst. Stress signals, such as UV radiation or ROS themselves, activate p66Shc, which was proposed to stimulate its H(2)O(2) forming activity, ultimately triggering mitochondrial disintegration. However, mechanistic details of H(2)O(2) formation and apoptosis induction by p66Shc and regulation of these activities remain to be revealed. Here, we describe the effects of Ser36 phosphorylation and Pin1 binding on p66Shc activity, and the identification of Peroxiredoxin 1 (Prx1) as a novel interaction partner for the unique p66Shc N-terminal domain. Prx1 was identified in affinity experiments as dominant interaction partner. Complex formation leads to disassembly of Prx1 decamers, which is known to increase its peroxidase activity. The interaction leads to reduction of the p66CH2CB tetramer, which reduces its ability to induce mitochondrial rupture. Our results indicate that p66CH2CB and Prx1 form a stress-sensing complex that keeps p66Shc inactive at moderate stress levels.
Gertz
Melanie
M
Department of Physiological Chemistry, Ruhr-University Bochum, 44801 Bochum, Germany.
Fischer
Frank
F
Leipelt
Martina
M
Wolters
Dirk
D
Steegborn
Clemens
C
D000818:Animals; D003001:Cloning, Molecular; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
D017382:Reactive Oxygen Species; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D054464:Peroxiredoxins