NFE2L1/Nrf1 forms a coactivator complex post-peptide:N-glycanase-mediated sequence editing and mitigates proteasome dysfunction

Nuclear factor erythroid 2-like 1 (NFE2L1/Nrf1), an endoplasmic reticulum (ER)-associated transcription factor, is responsible for the coordinated expression of proteasome subunit genes upon proteasomal dysfunction. N-glycosylated proteins undergo protein sequence editing by peptide:N-glycanase (NGLY1)-mediated conversion of N-glycosylated asparagine residues to aspartic acid. Nrf proteins are the only transcription factors that undergo sequence editing for transcriptional activation. However, the mechanism via which sequence editing regulates the transcriptional activity of Nrf1 has remained unclear. Here, we demonstrated that sequence editing of the ninth N-glycosylation site (Asn574) in human Nrf1 is required for proteasome gene expression in HeLa cells.