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

Kiyohiro Ando; Melissa J Parsons; Richa B Shah; Chloé I Charendoff; Sheré L Paris; Peter H Liu; Sara R Fassio; Brittany A Rohrman; Ruth Thompson; Andrew Oberst; Samuel Sidi; Lisa Bouchier-Hayes

doi:10.1083/jcb.201608095

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.

Authors

Kiyohiro Ando^{1

2}, Melissa J Parsons³, Richa B Shah^{1

2}, Chloé I Charendoff³, Sheré L Paris³, Peter H Liu^{1

2}, Sara R Fassio³, Brittany A Rohrman³, Ruth Thompson^{1

2}, Andrew Oberst⁴, Samuel Sidi^{5

2}, Lisa Bouchier-Hayes^{6

7}

Affiliations

¹ Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute at Mount Sinai, New York, NY 10029.
² Department of Developmental and Regenerative Biology and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
³ Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, TX 77030.
⁴ Department of Immunology, University of Washington, Seattle, WA 98109.
⁵ Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute at Mount Sinai, New York, NY 10029 lxbouchi@txch.org samuel.sidi@mssm.edu.
⁶ Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, TX 77030 lxbouchi@txch.org samuel.sidi@mssm.edu.
⁷ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.

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*
Nucleophosmin
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
NPM1 protein, human
Npm1 protein, mouse
Nuclear Proteins
PIDD1 protein, human
Pidd1 protein, mouse
Zebrafish Proteins
Nucleophosmin
CASP2 protein, human
Casp2 protein, mouse
Caspase 2
Cysteine Endopeptidases

Abstract

Publication types

MeSH terms

Substances

Grants and funding