Recovery of proteasome activity in cells pulse-treated with proteasome inhibitors is independent of DDI2

Abstract Rapid recovery of proteasome activity may contribute to intrinsic and acquired resistance to FDA-approved proteasome inhibitors. Previous studies have demonstrated that the expression of proteasome genes in cells treated with sub-lethal concentrations of proteasome inhibitors is upregulated by the transcription factor Nrf1 (NFE2L1), which is activated by a novel DDI2 protease. Here we demonstrate that the recovery of proteasome activity is DDI2-independent and occurs before the upregulation of proteasome gene expression. The recovery requires protein translation, but the efficiency of translation of proteasomal mRNA does not increase upon proteasome inhibition. Based on this data, we propose that the increased efficiency of proteasome assembly is responsible for the recovery of proteasome activity.