Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy

Abstract

Cells exposed to proteotoxic stress invoke adaptive responses aimed at restoring proteostasis. Our previous studies have established a firm role for the transcription factor Nuclear factor erythroid derived 2-related factor 1 (Nrf1, also called NFE2L1) in responding to proteotoxic stress elicited by inhibition of cellular proteasome. Following proteasome inhibition, Nrf1 mediates new proteasome synthesis, thus enabling the cells to mitigate the proteotoxic stress. Here we report that under similar circumstances, multiple components of the autophagy lysosomal pathway (ALP) are transcriptionally upregulated in an Nrf1-dependent fashion, thus providing the cells with an additional route to cope with proteasome insufficiency. In response to proteasome inhibitors, Nrf1-deficient cells displayed profound defects in invoking autophagy and clearance of aggresomes. This phenomenon was also recapitulated in NGLY1 knockout cells (a model for NGLY1 disease) where Nrf1 is known to be non-functional. Overall, our results significantly expand the role of Nrf1 in shaping the cellular response to proteotoxic stress.