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

Lookup NU author(s): Professor Matthias Trost

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2019 The Authors. Published under the terms of the CC BY 4.0 license 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 H 2 O 2 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.


Publication metadata

Author(s): Keuss MJ, Hjerpe R, Hsia O, Gourlay R, Burchmore R, Trost M, Kurz T

Publication type: Article

Publication status: Published

Journal: EMBO Journal

Year: 2019

Volume: 38

Print publication date: 15/03/2019

Online publication date: 25/02/2019

Acceptance date: 28/01/2019

Date deposited: 19/03/2019

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: Wiley-VCH Verlag

URL: https://doi.org/10.15252/embj.2018100024

DOI: 10.15252/embj.2018100024


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