Nrf2MAFF

Nrf2MAFF refers to the transcriptional complex formed by the transcription factor Nrf2 (NFE2L2) and the small Maf protein MAFF. In this pairing, Nrf2 provides the transactivation domain and DNA-binding specificity, while MAFF acts as a dimerization partner that stabilizes the DNA-binding complex. The Nrf2-MAFF heterodimer binds antioxidant response elements (ARE) in the promoter regions of a broad set of cytoprotective and detoxification genes, enabling transcriptional activation in response to oxidative or electrophilic stress.

Mechanism and function: Under normal conditions, Nrf2 is kept at low levels by KEAP1-directed ubiquitination and proteasomal degradation. When cells experience oxidative stress or electrophiles, Nrf2 escapes KEAP1, accumulates in the nucleus, and dimerizes with MAFF (as well as with other small Maf proteins like MAFG or MafK). The Nrf2-MAFF complex recruits transcriptional coactivators and the RNA polymerase II machinery to ARE-containing genes, upregulating pathways involved in glutathione synthesis, detoxification, and antioxidant defenses. Small Maf proteins, including MAFF, can also pair with other partners such as BACH1; in that context, they contribute to repression of ARE-driven genes, illustrating that the Maf family can participate in both activation and repression depending on the partner.

Biological significance: The Nrf2-MAFF axis is central to redox homeostasis and cellular defense against chemical stress. Target genes include NQO1, HMOX1, GCLC, GCLM, and various glutathione-S-transferases. Dysregulation of Nrf2-MAFF signaling has been linked to enhanced sensitivity to oxidative damage as well as to adaptive advantages in certain cancers, where constitutive Nrf2 activity can promote survival and chemoresistance. Pharmacological activation of the NRF2-MAFF pathway is an area of interest for therapies aimed at boosting antioxidant defenses.