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. 2014 Apr 2;9(4):e93458. doi: 10.1371/journal.pone.0093458

Figure 1. The NHB1-CNC subfamily of membrane-bound transcription factors.

Figure 1

(A) The structural domains of NF-E2 p45-related CNC-bZIP transcription factors have been identified by bioinformatic analyses of their amino acid sequences. The Neh4 and Neh5 domains, which act as transactivation domains (TADs) in Nrf2 [49], [75], are represented by Neh4L and Neh5L in other family proteins. In Nrf1, AD1 is an essential TAD, containing the PEST1, Neh2L, CPD and Neh5L subdomains (see Text). Neh2L contains the DIDLID/DLG element and the ETGE motif; both are present in CncC and Nrf2 where they regulate protein stability. In addition to AD1, the AD2 region also functions as a TAD in Nrf1 [6] and is conserved amongst all other CNC family members, where it has been labeled AD2L. The ER-targeting NHB1 peptide of Nrf1/TCF11 and its NST glycodomain [7] are represented in Nrf3, CncC and Skn-1. We propose that Nrf1, Nrf3, CncC and Skn-1 constitute a subfamily of CNC transcription factors, called NHB1-CNC, which are membrane-bound proteins that are glycosylated in the lumen of the ER. For definition of the major acronyms, see Box S1. (B) The conserved topological structure of NHB1-CNC factors within and around membranes is predicted by bioinfomatics. Their ER-targeting mechanism has been confirmed in Nrf1, Nrf3 and CncC [5], [11], to occur via the conserved TM1 motif. The ability of NHB1-CNC factors (except Skn-1) to bind ARE sequences in target gene promoter regions is mediated through their CNC/bZIP domains that are retained on the cyto/nucleoplasmic side of membranes. The DNA-binding activity of Skn-1 is attributed to its CNC domain [76]. The TADs of the membrane-bound factors are transiently translocated into the luminal side of the ER during the initial co-translactional topogenesis. When these factors are required to activate their target genes, the luminal TADs are repartitioned and dislocated/retrotranslocated out of the luminal side across membranes into the cytoplasmic and/or nucleoplasmic compartments, where they are presented to the general transcriptional machinery before transactivating target gene expression. In addition, the asterisk* indicates the presence of putative GSK-3 phosphorylation sites in Nrf1, TCF11 and Skn-1.