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.
© 2017 Ando et al.
MeSH terms
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Animals
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Apoptosis*
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CRADD Signaling Adaptor Protein / metabolism
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Caspase 2 / genetics
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Caspase 2 / metabolism*
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Cell Nucleolus / enzymology*
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / metabolism*
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DNA Damage*
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Death Domain Receptor Signaling Adaptor Proteins / genetics
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Death Domain Receptor Signaling Adaptor Proteins / metabolism*
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Enzyme Activation
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Genotype
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HEK293 Cells
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HeLa Cells
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Humans
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Mice, Knockout
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Microscopy, Confocal
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Microscopy, Fluorescence
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Microscopy, Video
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Multiprotein Complexes
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nucleophosmin
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Phenotype
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Protein Binding
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RNA Interference
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Signal Transduction
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Transfection
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Zebrafish / genetics
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Zebrafish / metabolism
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Zebrafish Proteins / genetics
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Zebrafish Proteins / metabolism
Substances
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CRADD Signaling Adaptor Protein
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CRADD protein, human
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Death Domain Receptor Signaling Adaptor Proteins
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Multiprotein Complexes
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NPM1 protein, human
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Npm1 protein, mouse
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Nuclear Proteins
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PIDD1 protein, human
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Pidd1 protein, mouse
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Zebrafish Proteins
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Nucleophosmin
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CASP2 protein, human
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Casp2 protein, mouse
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Caspase 2
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Cysteine Endopeptidases