Ando, K., Parsons, M.J. orcid.org/0000-0002-2131-9577, Shah, R.B. et al. (9 more authors) (2017) NPM1 directs PIDDosome-dependent caspase-2 activation in the nucleolus. The Journal of Cell Biology, 216 (6). pp. 1795-1810. ISSN 0021-9525
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 The Author(s). Reproduced in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 05 Jun 2017 15:47 |
Last Modified: | 05 Nov 2018 09:31 |
Published Version: | https://doi.org/10.1083/jcb.201608095 |
Status: | Published |
Publisher: | Rockefeller University Press |
Refereed: | Yes |
Identification Number: | 10.1083/jcb.201608095 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:117089 |