NRF1

Nrf1, also known as NFE2L1, is a basic leucine zipper (bZIP) transcription factor that belongs to the cap ‘n’ collar (CNC) family. It is encoded by the NRF1 gene in humans and is related to other CNC-bZIP factors such as Nrf2 (NFE2L2) and Nrf3 (NFE2L3). Nrf1 plays a key role in maintaining cellular proteostasis and redox balance, and it contributes to metabolic and mitochondrial gene regulation. It is essential for development in mammals, and its activity helps coordinate responses to proteasome impairment and endoplasmic reticulum (ER) stress. Nrf1 functions primarily as a transcriptional activator that drives expression of a subset of antioxidant and proteasome subunit genes, often in coordination with small Maf proteins.

Structure and localization: Nrf1 contains an N-terminal domain that anchors it to the endoplasmic reticulum membrane, and a C-terminal bZIP DNA-binding and transactivation region. In the cytosol, Nrf1 forms dimers with small Maf proteins and binds to antioxidant response elements (AREs) in target gene promoters. The ER tethering keeps Nrf1 in a poised state, and release and activation require regulated processing.

Activation and regulation: Under normal conditions, Nrf1 is retrotranslocated from the ER, deglycosylated, and processed to produce an active proteolytic fragment that translocates to the nucleus. This activation is strongly induced by proteasome inhibition or ER stress and involves processing by the protease DDI2, among other regulatory steps. Once in the nucleus, Nrf1 partners with AREs to induce transcription of target genes, including many proteasome subunits, supporting proteostasis and cellular adaptation to stress. Post-translational modifications, such as phosphorylation and ubiquitination, further modulate its activity.

Clinical and research context: Nrf1 is essential for development and organismal homeostasis. Its activity intersects with that of Nrf2 and other stress pathways. Dysregulation of Nrf1 has been implicated in various diseases, including cancer and neurodegenerative disorders, and it remains an active focus of research for understanding proteostasis and metabolic regulation.