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J Cell Biol ; 216(6): 1795-1810, 2017 06 05.
Article in English | MEDLINE | ID: mdl-28432080

ABSTRACT

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.


Subject(s)
Apoptosis , Caspase 2/metabolism , Cell Nucleolus/enzymology , Cysteine Endopeptidases/metabolism , DNA Damage , Death Domain Receptor Signaling Adaptor Proteins/metabolism , Nuclear Proteins/metabolism , Animals , CRADD Signaling Adaptor Protein/metabolism , Caspase 2/genetics , Cysteine Endopeptidases/genetics , Death Domain Receptor Signaling Adaptor Proteins/genetics , Enzyme Activation , Genotype , HEK293 Cells , HeLa Cells , Humans , Mice, Knockout , Microscopy, Confocal , Microscopy, Fluorescence , Microscopy, Video , Multiprotein Complexes , Nuclear Proteins/genetics , Nucleophosmin , Phenotype , Protein Binding , RNA Interference , Signal Transduction , Transfection , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism
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