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

-glycosylation sites other than Asn574 is required for the interaction with the coactivator CREBBP/EP300, thereby enhancing Nrf1's transcriptional activity. Unexpectedly, the expression of Nrf1 mutants that mimic proteolytic processing by DNA-damage-inducible 1 homolog 2 and sequence editing by NGLY1 markedly diminished the growth rate in HeLa cells, suggesting that the constitutive activation of Nrf1 exhibits cytotoxicity. Collectively, our study explains the strategy of on-demand Nrf1 activation for survival benefits. Nrf1 is synthesized as a proteasome-targeting protein and is highly glycosylated in the ER. Nrf1 is activated via sequence editing-dependent coactivator complex formation only when the proteasome needs to be compensated for.