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, (Accepted for Publication)

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, (Accepted for Publication)

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Abstract

NEDD8 is a ubiquitin-like protein that activates Cullin-RING E3 ubiquitin ligases (CRL). 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 de-neddylase 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 suggests 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:Accepted for Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hjerpe, Dr Roland and Burchmore, Dr Richard and Kurz, Dr Thimo 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 > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:EMBO Journal
Publisher:EMBO Press
ISSN:0261-4189
ISSN (Online):1460-2075

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