PUBLICATION
NPM1 directs PIDDosome-dependent caspase-2 activation in the nucleolus
- Authors
- Ando, K., Parsons, M.J., Shah, R.B., Charendoff, C.I., Paris, S.L., Liu, P.H., Fassio, S.R., Rohrman, B.A., Thompson, R., Oberst, A., Sidi, S., Bouchier-Hayes, L.
- ID
- ZDB-PUB-170914-5
- Date
- 2017
- Source
- The Journal of cell biology 216: 1795-1810 (Journal)
- Registered Authors
- Ando, Kiyohiro, Liu, Peter H., Sidi, Samuel, Thompson, Ruth
- Keywords
- none
- 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
- PubMed
- 28432080 Full text @ J. Cell Biol.
Citation
Ando, K., Parsons, M.J., Shah, R.B., Charendoff, C.I., Paris, S.L., Liu, P.H., Fassio, S.R., Rohrman, B.A., Thompson, R., Oberst, A., Sidi, S., Bouchier-Hayes, L. (2017) NPM1 directs PIDDosome-dependent caspase-2 activation in the nucleolus. The Journal of cell biology. 216:1795-1810.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping