NPM1 directs PIDDosome-dependent caspase-2 activation in the nucleolus

作者：Ando Kiyohiro; Parsons Melissa J; Shah Richa B; Charendoff Chloe I; Paris Shere L; Liu Peter H; Fassio Sara R; Rohrman Brittany A; Thompson Ruth; Oberst Andrew; Sidi Samuel^*; Bouchier Hayes Lisa^*

来源：The Journal of Cell Biology, 2017, 216(6): 1795-1810.

DOI：10.1083/jcb.201608095

The PIDDosome (PIDD-RAI DD-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 RAI DD dependent but PIDD independent, and a nucleolar platform that requires both PIDD and RAI DD. 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.

• 出版日期2017-6