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

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 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 and attenuated its activation. In cells in which Nedp1 is deleted, large amounts of tri-NEDD8 constitutively form, resulting in inhibition of Pduanyu37-1 and protection from cell death. Surprisingly, these NEDD8 trimers are additionally acetylated, as shown by mass spectrometry analysis, and their binding to Pduanyu37-1 is reduced by the overexpression of histone de-acetylases, which rescues Pduanyu37-1 activation. Our data suggest that trimeric, acetylated NEDD8 attenuates Pduanyu37-1 activation after oxidative stress, likely to delay the initiation of Pduanyu37-1-dependent cell death.

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