Activation of the lifespan regulator p66Shc through reversible disulfide bond formation.

Proceedings of the National Academy of Sciences of the United States of America
Melanie GertzClemens Steegborn

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.

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis