Autophagy inhibition engages Nrf2-p62 Ub-associated signaling

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Figure 1 Schematic of Ub-associated signaling regulated by the Nrf2-p62 axis. The Keap1-Cul3-Rbx1 E3 Ub ligase maintains low levels of Nrf2 in the cell. In response to oxidative insult, accumulation of misfolded, aggregation-prone proteins or additional unknown stressors, p62 levels increase. Interaction of p62 with the Keap1:Nrf2 binding pocket results in Nrf2 stabilization and nuclear translocation. Once in the nucleus, Nrf2—and its heterodimeric binding partner Maf (or additional undefined binding partners)—bind antioxidant response elements (ARE) to activate phase II antioxidant genes and Ub-associated genes. Resolution of the stress resets the Nrf2-p62 axis by returning Nrf2 and p62 back to low levels. In the presence of continual cellular stress, Nrf2 and p62 levels are constitutively elevated contributing to a feedback loop resulting in sustained activation of phase II antioxidant and Ub-related genes.

Punctum to: Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. J Cell Biol 2010; 191:537 - 552; PMID: 21041446; http://dx.doi.org/10.1083/jcb.201005012

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