Ando Kiyohiro, Parsons Melissa J, Shah Richa B, Charendoff Chloé I, Paris Sheré L, Liu Peter H, Fassio Sara R, Rohrman Brittany A, Thompson Ruth, Oberst Andrew, Sidi Samuel, Bouchier-Hayes Lisa
Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute at Mount Sinai, New York, NY 10029.
Department of Developmental and Regenerative Biology and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
J Cell Biol. 2017 Jun 5;216(6):1795-1810. doi: 10.1083/jcb.201608095. Epub 2017 Apr 21.
The PIDDosome (PIDD-RAIDD-caspase-2 complex) is considered to be the primary signaling platform for caspase-2 activation in response to genotoxic stress. Yet studies of PIDD-deficient mice show that caspase-2 activation can proceed in the absence of PIDD. Here we show that DNA damage induces the assembly of at least two distinct activation platforms for caspase-2: a cytoplasmic platform that is RAIDD dependent but PIDD independent, and a nucleolar platform that requires both PIDD and RAIDD. Furthermore, the nucleolar phosphoprotein nucleophosmin (NPM1) acts as a scaffold for PIDD and is essential for PIDDosome assembly in the nucleolus after DNA damage. Inhibition of NPM1 impairs caspase-2 processing, apoptosis, and caspase-2-dependent inhibition of cell growth, demonstrating that the NPM1-dependent nucleolar PIDDosome is a key initiator of the caspase-2 activation cascade. Thus we have identified the nucleolus as a novel site for caspase-2 activation and function.
PIDDosome（PIDD-RAIDD-半胱天冬酶-2复合物）被认为是响应基因毒性应激时半胱天冬酶-2激活的主要信号平台。然而，对PIDD基因缺陷小鼠的研究表明，在没有PIDD的情况下半胱天冬酶-2的激活仍可进行。在此我们表明，DNA损伤诱导了至少两个不同的半胱天冬酶-2激活平台的组装：一个细胞质平台，其依赖于RAIDD但不依赖于PIDD；以及一个核仁平台，其需要PIDD和RAIDD两者。此外，核仁磷蛋白核仁素（NPM1）作为PIDD的支架，并且在DNA损伤后对于核仁中PIDDosome的组装至关重要。抑制NPM1会损害半胱天冬酶-2的加工、凋亡以及半胱天冬酶-2依赖性的细胞生长抑制，表明NPM1依赖性的核仁PIDDosome是半胱天冬酶-2激活级联反应的关键启动子。因此，我们已确定核仁是半胱天冬酶-2激活和发挥功能的一个新位点。
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