The inhibition of the UPS results in the activation of autophagy. Inhibition of proteasomal degradation of target proteins increases the autophagy by the compensatory activation. Unfolded or misfolded proteins caused the ER stress, subsequently increasing the expression of ATG genes. In addition, the accumulation of unfolded or misfolded proteins stimulates the phosphorylation of p62 by ULK1. Phosphorylation of p62 positively modulates the binding of p62 to polyubiquitinated proteins and the recruitment of autophagy machinery to the target protein. Deficiency of proteasome components or the suppression of its activity was known to induce the transcriptional and translational expression of p62 and the p62 protein through the activation of transcription factor Nrf2. In summary, Nrf2 increases the transcription of p62, and the increased p62 binds to and stabilizes Nrf2, which then continually regulates the levels of p62 and Nrf2 through the positive feedback mechanism.
