PIDD death-domain phosphorylation by ATM controls prodeath versus prosurvival PIDDosome signaling.

Biochemical evidence implicates the death-domain (DD) protein PIDD as a molecular switch capable of signaling cell survival or death in response to genotoxic stress. PIDD activity is determined by binding-partner selection at its DD: whereas recruitment of RIP1 triggers prosurvival NF-?B signaling, recruitment of RAIDD activates proapoptotic caspase-2 via PIDDosome ...
formation. However, it remains unclear how interactor selection, and thus fate decision, is regulated at the PIDD platform. We show that the PIDDosome functions in the "Chk1-suppressed" apoptotic response to DNA damage, a conserved ATM/ATR-caspase-2 pathway antagonized by Chk1. In this pathway, ATM phosphorylates PIDD on Thr788 within the DD. This phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation. Conversely, nonphosphorylatable PIDD fails to bind RAIDD or activate caspase-2, and engages prosurvival RIP1 instead. Thus, ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury.
Mesh Terms:
Ataxia Telangiectasia Mutated Proteins, CRADD Signaling Adaptor Protein, Caspase 2, Cell Cycle Proteins, Cell Death, Cell Survival, Cells, Cultured, DNA Damage, DNA-Binding Proteins, Death Domain Receptor Signaling Adaptor Proteins, HEK293 Cells, HeLa Cells, Humans, Phosphorylation, Protein Serine-Threonine Kinases, Signal Transduction, Tumor Suppressor Proteins
Mol Cell
Date: Sep. 14, 2012
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