Unanchored tri-NEDD8 inhibits PARP-1 to protect from oxidative stress-induced cell death

Keuss, M. J., Hjerpe, R., Hsia, O., Gourlay, R., Burchmore, R. , Trost, M. and Kurz, T. (2019) Unanchored tri-NEDD8 inhibits PARP-1 to protect from oxidative stress-induced cell death. EMBO Journal, 38, e100024. (doi: 10.15252/embj.2018100024) (PMID:30804002) (PMCID:PMC6418418)

Abstract

NEDD8 is a ubiquitin‐like protein that activates cullin‐RING E3 ubiquitin ligases (CRLs). Here, we identify a novel role for NEDD8 in regulating the activity of poly(ADP‐ribose) polymerase 1 (PARP‐1) in response to oxidative stress. We show that treatment of cells with H2O2 results in the accumulation of NEDD8 chains, likely by directly inhibiting the deneddylase NEDP1. One chain type, an unanchored NEDD8 trimer, specifically bound to the second zinc finger domain of PARP‐1 and attenuated its activation. In cells in which Nedp1 is deleted, large amounts of tri‐NEDD8 constitutively form, resulting in inhibition of PARP‐1 and protection from PARP‐1‐dependent cell death. Surprisingly, these NEDD8 trimers are additionally acetylated, as shown by mass spectrometry analysis, and their binding to PARP‐1 is reduced by the overexpression of histone de‐acetylases, which rescues PARP‐1 activation. Our data suggest that trimeric, acetylated NEDD8 attenuates PARP‐1 activation after oxidative stress, likely to delay the initiation of PARP‐1‐dependent cell death.

• Item Type: Articles
• Additional Information: MT was funded by the Medical Research Council (MC_UU_12016/5), work in the TK laboratory is supported by grants from Motor Neurone Disease Scotland and the British Council BIRAX initiative.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kurz, Dr Thimo and Hjerpe, Dr Roland and Burchmore, Dr Richard and Hsia, Oliver and Keuss, Dr Rer Nat Matthew
• Authors: Keuss, M. J., Hjerpe, R., Hsia, O., Gourlay, R., Burchmore, R., Trost, M., and Kurz, T.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: EMBO Journal
• Publisher: EMBO Press
• ISSN: 0261-4189
• ISSN (Online): 1460-2075
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in EMBO Journal 38:e100024
• Publisher Policy: Reproduced under a Creative Commons License