Activation of the lifespan regulator p66 Shc through reversible disulfide bond formation

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Abstract
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.