Arkadia (RING finger protein 111) mediates sumoylation‐dependent stabilization of Nrf2 through K48‐linked ubiquitylation

Abstract

The transcription factor Nrf2 is a master regulator of the antioxidant defense system that serves to protect cells from oxidative damage. We previously reported that the SUMO‐targeted E3 ubiquitin ligase (STUbL), RING finger protein 4 (RNF4) accelerated the degradation rate of Nrf2 in promyelocytic leukemia‐nuclear body (PML‐NB)‐enriched fractions and decreased Nrf2‐mediated gene transcription. STUbLs contain SUMO‐interaction motifs that enable it to target substrate proteins that have been modified by SUMO resulting in ubiquitylation. These ubiquitylation events help in regulating eukaryotic cellular activity. In this study, we establish the second mammalian STUbL, Arkadia/RNF111 ubiquitylates polysumolyated Nrf2 to stabilize it, but has no effect on Nrf2‐mediated gene transcription. Interestingly, we discovered that the Arkadia‐mediated stabilization of Nrf2 occurs through Ub‐K48 linkages rather than the predicted Ub‐K63 linkages. These results suggest Arkadia‐mediated ubiquitylation of Nrf2 protects it from degradation, thereby allowing Nrf2‐dependent gene transcription. Collectively, these findings highlight a novel mechanism to positively regulate nuclear Nrf2 levels in response to oxidative stress.Support or Funding InformationThis work was supported by NIH grant SC1CA143985 and by CTSA award No. ULITR000445 from the National Center for Advancing Translational Sciences. +Supported by NIH grant # 2 S21MD000104This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.