Topovectorial mechanisms control the juxtamembrane proteolytic processing of Nrf1 to remove its N-terminal polypeptides during maturation of the CNC-bZIP factor

Abstract

ABSTRACT

Nrf1D is the first candidate secretory transcription factor in the blood plasma, with its precursor existing as a unique redox-sensitive transmembrane CNC-bZIP protein in somatic tissues

“…In combination with our previous studies of Nrf1 [9,18,[25][26][27], the evidence that has been presented here, reveals that Nrf1D is integrated in dynamic membrane-topologies within and around the ER (Fig. 8B), which are predominantly determined by both its N-terminal signal anchor (i.e.…”

“…To give a better interpretation of Nrf1 topobiology, a model (Fig. 8A) is proposed on the basis of ever-accumulating evidence obtained from previous studies by us [9,18,[25][26][27] and other groups [28][29][30]. Upon translation of Nrf1, its newly-synthesized polypeptide is targeted and anchored within ER membranes through its NHB1 signal peptide, spinning in an Ncyto/Clum orientation (i.e.…”

“…Such modified Nrf1 protein is then subjected to the selective proteolytic processing to remove distinct lengths of its N-terminal portions by cytosolic DDI-1/2 protease-mediated cleavage and/or 26S proteasome -limited degradation. In turn, transcriptional expression of p97, DDI-1, and proteasomal genes is predominantly regulated by processed mature Nrf1 factor through coupled positive and negative feedback circuits [26,27]. In addition, Nrf1 is also likely sorted out of the ER membrane and transported in the inner nuclear membrane to gain a direct access to target genes [25].…”

“…Of note, distinct topovectorial processes of Nrf1 dictates its post-translational modifications and selective proteolytic processing to yield multiple isoforms, as well as its transcriptional activity to mediate target gene expression. In turn, expression of Nrf1-target p97, DDI-1, and proteasomal genes is also predominantly regulated by processed mature Nrf1 factor through coupled positive and negative feedback circuits [26,27]. (B) Another similar but different model is introduced to explain topobiology of Nrf1D, that has a unique redox-sensitive TMc module spinning the ER membrane with an Nlum/Ccyto orientation.…”

Oncogenic activation of Nrf2 by specific knockout of Nrf1α that acts as a dominant tumor repressor

“…In these topovectorial processes of Nrf1α, it is subjected to specific post-translational modifications (e.g. glycosylation, deglycosylation, ubiquitination), and also selective juxtamembrane proteolytic processing of the CNC-bZIP factor so as to yield multiple isoforms with different and opposing activities, during maturation into an activator (Koizumi et al, 2016;Xiang et al, 2018a;Xiang et al, 2018b). In addition, distinct variants of Nrf1, including its long TCF11, short Nrf1/LCR-F1 and small dominantnegative Nrf1/, are also generated by alternative translation from various lengths of alternatively-spliced mRNA transcripts (Zhang et al, 2014a).…”