An Inhibitor of PIDDosome Formation.
An Inhibitor of PIDDosome Formation.
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PIDDosome 形成的抑制剂。
DOI：
10.1016/j.molcel.2015.03.034
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发表时间：
2015
期刊：
影响因子：
16
通讯作者：
Sidi,Samuel
中科院分区：
文献类型：
--
作者：
Thompson,Ruth;Shah,RichaB;Liu,PeterH;Gupta,YogeshK;Ando,Kiyohiro;Aggarwal,AneelK;Sidi,Samuel
PIDDosome-PIDD-RAIDD-caspase-2复合物-是一种具有难以捉摸的意义的促凋亡caspase-激活平台。DNA损伤可以通过PIDD死亡结构域（DD）的ATM磷酸化启动复合物组装，这使得RAIDD能够募集到PIDD。相反，限制PIDDosome形成的机制仍不清楚。我们确定了有丝分裂检查点因子BubR 1作为一个直接的PID Dosome抑制剂，在一个非经典的作用，独立于Mad 2。在DNA断裂处被ATM磷酸化后，“引发的”PIDD通过与BubR 1的直接相互作用重新定位到着丝粒。BubR 1结合PIDDD，与RAIDD募集竞争，并在电离辐射后否定PIDDosome介导的凋亡。因此，PIDDosome顺序整合DNA损伤和有丝分裂检查点信号，以决定细胞命运，以响应遗传毒性应激。我们进一步表明，通过在动粒处隔离PIDD，BubR 1起到延迟PIDDosome形成直到下一个周期的作用，从而定义了细胞在有丝分裂期间逃避凋亡的新机制。
The PIDDosome—PIDD-RAIDD-caspase-2 complex—is a proapoptotic caspase-activation platform of elusive significance. DNA damage can initiate complex assembly via ATM phosphorylation of the PIDD death domain (DD), which enables RAIDD recruitment to PIDD. In contrast, the mechanisms limiting PIDDosome formation have remained unclear. We identify the mitotic checkpoint factor BubR1 as a direct PIDDosome inhibitor, acting in a noncanonical role independent of Mad2. Following its phosphorylation by ATM at DNA breaks, "primed" PIDD relocates to kinetochores via a direct interaction with BubR1. BubR1 binds the PIDD DD, competes with RAIDD recruitment, and negates PIDDosome-mediated apoptosis after ionizing radiation. The PIDDosome thus sequentially integrates DNA damage and mitotic checkpoint signals to decide cell fate in response to genotoxic stress. We further show that by sequestering PIDD at the kinetochore, BubR1 acts to delay PIDDosome formation until the next cycle, defining a new mechanism by which cells evade apoptosis during mitosis.