Activation, interaction and intimation of Nrf2 pathway and their mutational studies causing Nrf2 associated cancer

Abstract

Responses against infection trigger several signaling pathways that lead to the production of cytokines, these cytokines release ROS and RNS, damaging DNA and proteins turn into various diseases including cancer. To combat these harmful cytokines, the Nrf2 pathway is activated. The gene NFE2L2 encodes Nrf2, which is divided into seven conserved domains (Neh1–7). The DLG and ETGE motifs, conserved sequences of amino acid in the Neh2 domain of Nrf2, bind to the BTB domain of Keap1. BTB domain promotes Keap1's homodimerization resulting in Cul3 recruitment providing scaffold formation to E2 ubiquitin ligase to form ubiquitin complex. Under normal conditions, this complex regularly degrades Nrf2. However, once the cell is exposed to oxidative stress by ROS interaction with Keap1 resulting in conformational changes that stabilize the Nrf2. Nrf2 further concentrates on the nucleus where it binds with the transcriptional factor to perform the desired genes transcription for synthesizing SOD, GSH, CAT, and various other proteins which reduce the ROS levels preventing certain diseases. To prevent cells from oxidative stress, molecular hydrogen activates the Nrf2 pathway. To activate the Nrf2 pathway, molecular hydrogen oxidizes the iron porphyrin which acts as an electrophile and interacts with Keap1's cysteine residue.