Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks

Figure 11

An integral model to interpret coordinated regulation of distinct cellular respiratory and antioxidant gene transcription networks. (a) A model is based on our experimental evidence, to give a better understanding of regulatory cross-talk among Nfe2l1^Nrf1, Nfe2l2^Nrf2, α-Pal^NRF1, and Pitx2, all targeting TFAM. During the nuclear-to-mitochondrial communication, Nfe2l1^Nrf1 makes opposing contributions to bidirectional regulation of Nfe2l2^Nrf2 and α-Pal^NRF1 by itself and target proteasome (PSM) at two distinct layers. Nfe2l2^Nrf2 can determine posttranscriptional regulation of Nfe2l1^Nrf1 and α-Pal^NRF1, but the detailed mechanism remains unclear. In turn, mouse α-Pal^NRF1 contributes to positive regulation of Nfe2l1^Nrf1 and Nfe2l2^Nrf2, although no canonic GC-rich α-Pal-binding sites exist in these mouse CNC-bZIP gene promoter regions (Table S2). Contrarily, human α-Pal^NRF1 makes a negative contribution to transcriptional expression of Nfe2l1^Nrf1 and Nfe2l2^Nrf2 (the latter Nfe2l2^Nrf2 is dominantly negatively regulated by human Nfe2l1^Nrf1), albeit all three factors are activated by redox inducer tBHQ. In addition to negative regulation of Nfe2l2^Nrf2 by Keap1, the adaptor subunit of Cullin 3-based E3 ubiquitin ligase can also make a positive contribution to transcriptional regulation of mouse Nfe2l2^Nrf2, rather than Nfe2l1^Nrf1, as found in MEFs. However, human Nfe2l1^Nrf1 is essential for stabilization of Keap1, but it is unknown whether this adaptor protein is involved in the proteolytic processing of Nfe2l1^Nrf1. Notably, the nucleus-controlled mitochondrial respiratory and oxidative phosphorylation are also a primary source of ROS in cells, which triggers activation of Nfe2l1^Nrf1, Nfe2l2^Nrf2, and α-Pal^NRF1 to certain extents so that cellular redox homeostasis is maintained at a steady state. Besides, GABP^NRF2 is also required for this process, but possible cross-talks of this ETS family factor with Nfe2l1^Nrf1 and Nfe2l2^Nrf2 are not yet identified here. The “M”-marked arrowheads indicate those activity in the mouse but not in the human; such distinction was also shown (in Figure S2). (b) Schematic explanation of the intracellular redox homeostasis balanced by an oxidative respiratory system and another antioxidant cytoprotective response. Most of ARE-driven genes are transcriptionally regulated by distinct functional heterodimers of either Nfe2l1^Nrf1or Nfe2l2^Nrf2 with sMaf or other bZIP proteins, whilst most of the nucleus-encoded mitochondrial respiratory genes are controlled predominantly by α-Pal^NRF1 homodimers. Of note, the GC-enriched α-Pal-binding site is overlapped with the -GC-motif of ARE-core sequences (each of which contains an AP-1 site). This implies synergistic and/or antagonistic regulatory effects of Nfe2l1^Nrf1, Nfe2l2^Nrf2, and α-Pal^NRF1 on certain expression of distinct cognate target genes. (c) Schematic representation of distinct structural domains of Nfe2l1^Nrf1, Nfe2l2^Nrf2, and α-Pal^NRF1, as well as GABPα^NRF2, GABPβ1L^NRF2, GABPβ1S^NRF2, and GABPβ2^NRF2. Of note, all domains and motifs of Nfe2l1^Nrf1 and Nfe2l2^Nrf2 were defined (37), but neither have no homology with α-Pal^NRF1, GABPα^NRF2, and GABPβ^NRF2. Distinct domains and motifs of these nuclear respiratory factors are identified by bioinformatic analysis of their amino-acid sequences. ANK: ankyrin repeats; DBD: DNA-binding domain; ER: endoplasmic reticulum; ETS: E26 transformation specific; GSD: GABPα-specific domain; NLS: nuclear localization signal; Mito: mitochondria; SAM: sterile α-motif pointed domain; TAD: transactivation domain.

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