Transcription factor Nrf1 is topologically repartitioned across membranes to enable target gene transactivation through its acidic glucose-responsive domains.
The membrane-bound Nrf1 transcription factor regulates critical homeostatic and developmental genes. The conserved N-terminal homology box 1 (NHB1) sequence in Nrf1 targets the cap'n'collar (CNC) basic basic-region leucine zipper (bZIP) factor to the endoplasmic reticulum (ER), but it is unknown how its activity is controlled topologically within membranes. Herein, we report a hitherto unknown mechanism by which the transactivation activity of Nrf1 is controlled through its membrane-topology. Thus after Nrf1 is anchored within ER membranes, its acidic transactivation domains (TADs), including the Asn/Ser/Thr-rich (NST) glycodomain situated between acidic domain 1 (AD1) and AD2, are transiently translocated into the lumen of the ER, where NST is glycosylated in the presence of glucose to yield an inactive 120-kDa Nrf1 glycoprotein. Subsequently, portions of the TADs partially repartition across membranes into the cyto/nucleoplasmic compartments, whereupon an active 95-kDa form of Nrf1 accumulates, a process that is more obvious in glucose-deprived cells and may involve deglycosylation. The repartitioning of Nrf1 out of membranes is monitored within this protein by its acidic-hydrophobic amphipathic glucose-responsive domains, particularly the Neh5L subdomain within AD1. Therefore, the membrane-topological organization of Nrf1 dictates its post-translational modifications (i.e. glycosylation, the putative deglycosylation and selective proteolysis), which together control its ability to transactivate target genes.
The NSFC-funded Laboratory of Cell Biochemistry and Gene Regulation, College of Medical Bioengineering and Faculty of Life Sciences, Chongqing University, Chongqing, China; Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Scotland, United Kingdom.
Yiguo
Y
Zhang
The NSFC-funded Laboratory of Cell Biochemistry and Gene Regulation, College of Medical Bioengineering and Faculty of Life Sciences, Chongqing University, Chongqing, China.
Yonggang
Y
Ren
The NSFC-funded Laboratory of Cell Biochemistry and Gene Regulation, College of Medical Bioengineering and Faculty of Life Sciences, Chongqing University, Chongqing, China.
Shaojun
S
Li
Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, University of Dundee, Scotland, United Kingdom.
John D
JD
Hayes
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D008566:Membranes / Q000378:metabolism*; D008969:Molecular Sequence Data; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics* / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D059748:Proteolysis; D017386:Sequence Homology, Amino Acid; D015533:Transcriptional Activation / Q000235:genetics*
D051266:Nuclear Respiratory Factor 1; D005947:Glucose