Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Mol Cell. 2012 Sep 14;47(5):681-93. doi: 10.1016/j.molcel.2012.06.024. Epub 2012 Jul 30.
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.
生化证据表明，死亡结构域（DD）蛋白 PIDD 是一种分子开关，能够在应对遗传毒性应激时，发出细胞存活或死亡的信号。PIDD 活性取决于其 DD 的结合伙伴选择：RIP1 的募集触发了生存的 NF-κB 信号，而 RAIDD 的募集则通过 PIDDosome 的形成激活了促凋亡的 caspase-2。然而，目前尚不清楚在 PIDD 平台上如何调节相互作用体的选择，从而决定命运。我们发现，PIDDosome 在 DNA 损伤的“Chk1 抑制”凋亡反应中发挥作用，这是一种 ATM/ATR-caspase-2 途径，被 Chk1 拮抗。在这条途径中，ATM 在 DD 内的 Thr788 处磷酸化 PIDD。这种磷酸化对于 RAIDD 的结合和 caspase-2 的激活是必需和充分的。相反，不可磷酸化的 PIDD 无法结合 RAIDD 或激活 caspase-2，而是与生存的 RIP1 结合。因此，ATM 对 PIDD DD 的磷酸化通过一个二元开关使细胞在 DNA 损伤时选择存活或死亡。
