title: PIDD death-domain phosphorylation by ATM controls prodeath versus prosurvival PIDDosome signaling.
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.
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Kiyohiro
authors.initials: K
authors.lastname: Ando
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Kernan
authors.forename: Peter H
authors.initials: PH
authors.lastname: Liu
authors.forename: Takaomi
authors.initials: T
authors.lastname: Sanda
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Logette
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: Jianlong
authors.initials: J
authors.lastname: Wang
authors.forename: Lisa
authors.initials: L
authors.lastname: Bouchier-Hayes
authors.forename: Samuel
authors.initials: S
authors.lastname: Sidi
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D053420:CRADD Signaling Adaptor Protein / Q000378:metabolism; D053143:Caspase 2 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D053420:CRADD Signaling Adaptor Protein; C104252:CRADD protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; C485896:PIDD1 protein, human; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D053143:Caspase 2