Effect of cellular ubiquitin levels on the regulation of oxidative stress response and proteasome function via Nrf1

The polyubiquitin genes Ubb and Ubc are upregulated under oxidative stress induced by arsenite [As(III)]. However, the role of ubiquitin (Ub) under As(III) exposure is not known in detail. In a previous study, we showed that the reduced viability observed in Ubc−/− mouse embryonic fibroblasts under As(III) exposure was not due to dysregulation of the Nrf2–Keap1 pathway, which prompted us to investigate another NFE2 family protein, nuclear factor erythroid 2-related factor 1 (Nrf1). In this study, we found that Ub deficiency due to Ubc knockdown in N2a cells reduced cell viability and proteasome activity under As(III) exposure. Furthermore, mRNA levels of the proteasome subunit Psma1 were also reduced. In addition, Ub deficiency led to the nuclear accumulation of the p65 isoform of Nrf1 under As(III) exposure. Interestingly, the overexpression of p65-Nrf1 recapitulated the phenotypes of Ub-deficient N2a cells under As(III) exposure. On the other hand, Nrf1 knockdown suppressed the death of Ub-deficient N2a cells upon exposure to As(III). Therefore, the levels of p65-Nrf1 may play an important role in the maintenance of cell viability under oxidative stress induced by As(III). •N2a cells exhibit reduced viability upon exposure to As(III) via Ubc knockdown.•As(III)-induced proteasomal regulation is impaired in Ub-deficient N2a cells.•Ub deficiency leads to the nuclear accumulation of p65-Nrf1 under As(III) exposure.•p65 expression recapitulates As(III)-induced phenotypes of Ub-deficient N2a cells.•Nrf1 knockdown suppressed As(III)-induced death of Ub-deficient N2a cells.