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

Matthew J. Keuss, Roland Hjerpe, Oliver Hsia, Robert Gourlay, Richard Burchmore, Matthias Trost, Thimo Kurz (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)
102 Downloads (Pure)

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.
Original languageEnglish
Article number e100024
Pages (from-to)1-21
Number of pages21
JournalEMBO Journal
Volume38
Issue number6
Early online date25 Feb 2019
DOIs
Publication statusPublished - 15 Mar 2019

Keywords

  • NEDD8
  • PARP-1
  • cell death
  • oxidative stress
  • parthanatos

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