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

J Cell Biol. 2017 Jun 5;216(6):1795-1810. doi: 10.1083/jcb.201608095. Epub 2017 Apr 21.

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.

Publication types

  • Video-Audio Media

MeSH terms

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

Substances

  • CRADD Signaling Adaptor Protein
  • CRADD protein, human
  • Death Domain Receptor Signaling Adaptor Proteins
  • Multiprotein Complexes
  • Nuclear Proteins
  • PIDD1 protein, human
  • Pidd1 protein, mouse
  • Zebrafish Proteins
  • nucleophosmin
  • CASP2 protein, human
  • Casp2 protein, mouse
  • Caspase 2
  • Cysteine Endopeptidases