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

The EMBO Journal
Matthew J KeussThimo Kurz

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.

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Citations

Jul 28, 2020·Biomolecules·Wolfgang DubielMichael Naumann
Aug 1, 2019·Cellular and Molecular Life Sciences : CMLS·Hiroshi Ageta, Kunihiro Tsuchida
Feb 6, 2020·Nature Structural & Molecular Biology·Annette M VoglMorgan Sheng
Oct 8, 2020·Biomolecules·Maryia Karpiyevich, Katerina Artavanis-Tsakonas
Jan 5, 2021·Frontiers in Physiology·Jie LiHuabo Su
Apr 4, 2021·Biomolecules·Dana Harshuk-ShabsoElah Pick
Apr 9, 2021·Journal of Hematology & Oncology·Yi-Chao ZhengHong-Min Liu
Oct 14, 2021·Nature Communications·Katrin StuberMartin Scheffner
Nov 28, 2021·Autophagy·Debasish Kumar Ghosh, Akash Ranjan

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Methods Mentioned

BETA
neddylation
increased
pulldowns
pulldown
immunoprecipitation
transfection
immunoprecipitations
electrophoresis
acetylation
histone acetylation

Software Mentioned

ImageJ
Mascot
Proteome
Scaffold
GraphPad Prism
Proteome Discoverer
MaxQuant

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