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

Mol Cell. 2012 Sep 14;47(5):681-93. doi: 10.1016/j.molcel.2012.06.024. Epub 2012 Jul 30.

Abstract

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-κB 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • CRADD Signaling Adaptor Protein / metabolism
  • Caspase 2 / metabolism
  • Cell Cycle Proteins / metabolism*
  • Cell Death
  • Cell Survival
  • Cells, Cultured
  • DNA Damage
  • DNA-Binding Proteins / metabolism*
  • Death Domain Receptor Signaling Adaptor Proteins / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • CRADD Signaling Adaptor Protein
  • CRADD protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • PIDD1 protein, human
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Caspase 2