Molecular and cellular basis for the unique functioning of Nrf1, an indispensable transcription factor for maintaining cell homoeostasis and organ integrity

Abstract

The consensuscis-regulatory AP-1 (activator protein-1)-like AREs (antioxidant-response elements) and/or EpREs (electrophile-response elements) allow for differential recruitment of Nrf1 [NF-E2 (nuclear factor-erythroid 2)-related factor 1], Nrf2 and Nrf3, together with each of their heterodimeric partners (e.g. sMaf, c-Jun, JunD or c-Fos), to regulate different sets of cognate genes. Among them, NF-E2 p45 and Nrf3 are subject to tissue-specific expression in haemopoietic and placental cell lineages respectively. By contrast, Nrf1 and Nrf2 are two important transcription factors expressed ubiquitously in various vertebrate tissues and hence may elicit putative combinational or competitive functions. Nevertheless, they have de facto distinct biological activities because knockout of their genes in mice leads to distinguishable phenotypes. Of note, Nrf2 is dispensable during development and growth, albeit it is accepted as a master regulator of antioxidant, detoxification and cytoprotective genes against cellular stress. Relative to the water-soluble Nrf2, less attention has hitherto been drawn to the membrane-bound Nrf1, even though it has been shown to be indispensable for embryonic development and organ integrity. The biological discrepancy between Nrf1 and Nrf2 is determined by differences in both their primary structures and topovectorial subcellular locations, in which they are subjected to distinct post-translational processing so as to mediate differential expression of ARE-driven cytoprotective genes. In the present review, we focus on the molecular and cellular basis for Nrf1 and its isoforms, which together exert its essential functions for maintaining cellular homoeostasis, normal organ development and growth during life processes. Conversely, dysfunction of Nrf1 results in spontaneous development of non-alcoholic steatohepatitis, hepatoma, diabetes and neurodegenerative diseases in animal models.

Recent Insights into the Role of Unfolded Protein Response in ER Stress in Health and Disease

“…NRF1 shares many of its activities with the related factor NRF2, but NRF1 can specifically increase proteins associated with the proteasomes to promote protein degradation. NRF1 can be activated by different factors and events including ER stress (Zhang and Xiang, 2016). Recent studies showed that NRF1 is induced downstream of the target of rapamycin complex-1 (mTORC1) protein that is usually associated with the stimulation of protein synthesis and anabolic processes in the cell.…”

Redox regulation of proteasome function

“…Impairment of Keap1 and Nrf2 leads cells to reduced response or to Nrf2overactivation [6]. Upon proteasome inhibition, Nrf1 forms heterodimers with small Mafs on the ARE of proteasome subunits to promote their gene expression [9]. Under normal conditions, Nrf1 is located in the ER and degraded by the proteasome.…”

A unity of opposites in between Nrf1- and Nrf2-mediated responses to the endoplasmic reticulum stressor tunicamycin

“…Clearly, it is generally accepted that redox responses are mediated by two important antioxidant transcription factors Nrf1 [i.e. nuclear factor erythroid 2 (NF-E2) p45-related factor 1, also called Nfe2l1] and Nrf2 [8]. These two members of the cap'n'collar (CNC) basic-region leucine zipper (bZIP) family can predominantly regulate transcription of antioxidant response element (ARE)-driven genes involved in detoxification and other cytoprotective adaptations.…”

“…This implies a potential molecular compensatory mechanism, because E-and F-isoforms of Nrf1 may be generated by translation of a shorter-length open reading frame of mRNA resulting from the alternative first exon (i.e. Nrf1 N ) [8,24], in addition to proteolytic processing of longer Nrf1 isoforms. Intriguingly, almost no expression of the Nrf1-truncated E-isoform was determined in both cell lines of Nrf2 /TA and caNrf2 N , but they gave a modest decrease in abundance of Nrf1 F-form.…”