ArticleRedox biology2026
Dual promoter architecture of NFE2L2 underlies isoform-specific translational control of NRF2.
Article in Redox biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Transcription factor NRF2 (encoded by the NFE2L2 gene) is a central signalling hub that coordinates antioxidant, detoxification, anti-inflammatory and metabolic programmes to maintain cellular homeostasis, with broad relevance to degenerative diseases, chronic inflammation and cancer. NFE2L2 is transcribed from two promoters: the canonical promoter (P1) and an alternative promoter (P2), generating transcripts that differ solely in their first exon. Exon 1 of P1-derived transcripts contains the AUG start codon, whereas the considerably longer exon 1' of P2-derived transcripts forms an extended 5' untranslated region (5'UTR). Consequently, the P1-derived NRF2 isoform 1 contains 16 additional N-terminal amino acids relative to the P2-derived isoform 2. Although transcripts from both promoters are expressed in human tissues, the existence of isoform 2 protein and the functional significance of alternative promoter usage have remained unresolved. Here, we identify an endogenous NRF2 protein species consistent with isoform 2 using an isoform-specific siRNA strategy. Isoform 2 is negatively regulated by KEAP1 and retains the ability to activate canonical NRF2 target genes. Despite similar stability of the two isoforms, isoform 2 accumulates at substantially lower basal levels, which is associated with reduced translational engagement of P2-derived transcripts. Polysome profiling revealed that P1-derived transcripts are predominantly associated with polysomes, whereas P2-derived transcripts are distributed between polysomal and subpolysomal fractions. The extended P2-specific 5'UTR contains evolutionarily conserved structural features that may contribute to translational regulation. Finally, the electrophilic NRF2 activator omaveloxolone (RTA-408) induced translation of transcripts from both promoters, demonstrating that NRF2 stress response is coordinated through the combined regulation of mRNA translation and protein stability.
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