Molecular and Cellular Control of the Nrf1 Transcription Factor

This study has revealed that Nrf1 is an integral§membrane glycoprotein with transmembrane and§extramembrane regions, located in both the§endoplasmic reticulum (ER) and the nuclear envelope.§This CNC/bZIP protein is targeted and anchored in the§ER through its N-terminal Homology Box 1 (NHB1)§sequence, and in the ER lumen it is glycosylated by§amide-linked attachment of glycans to the asparagines§within its NST domain. After being correctly folded§into a proper topology, mature Nrf1 protein could be§sorted out into the nuclear envelope. Once reaching§the inner nuclear membrane, it can gain access to the§promoter regions of its target genes and relevant§transcriptional mechineries in the nucleoplasm. It§should be noted that, although Nrf1 is integrated in§the ER membrane, it is not activated by ER stressors,§and conversely,they were found§to inhibit activation of this factor by a redox§inducer tBHQ. Therefore, Nrf1 may function§essentially as a control of redox compartmentization§for maintaining redox homeostasis between the ER and§nucleus; the former is a more oxidizing environment§in the cell, whereas the latter is a more reducing §conpartment.