Regulation of the Keap1–Nrf2 pathway by p62/SQSTM1

AbstractNrf2 is a transcription factor responsible for gene expression of a series of anti-oxidant proteins and detoxifying enzymes. Keap1, an adaptor protein of Cullin-3 ubiquitin ligase, senses electrophilic or oxidative stresses and then arrests ubiquitination of Nrf2, leading to Nrf2 activation. In addition to this canonical pathway, one Nrf2 target (p62/SQSTM1) competitively binds to Keap1 to activate Nrf2. The p62/SQSTM1-Keap1-Nrf2 axis is linked to selective autophagy and regulated by post-translational modifications such as sequential phosphorylation and ubiquitination of p62/SQSTM1. Importantly, this non-canonical pathway is hyper-activated in autophagy-deficient mouse livers and tissues of hepatocellular carcinoma. In this review, we delineate a molecular mechanism of Nrf2-activation by p62/SQSTM1, and describe its physiological role as well as the pathophysiological significance in autophagy-knockout livers and human hepatocellular carcinoma