Figure 1. Schematic on the role of ubiquitin proteasome pathway (UPP) imbalance in chronic diseases.

Under normal conditions, optimal activation of UPP balances Nrf2 and IκB (endogenous inhibitor of NF-κB) levels so that there is no induction of antioxidant and inflammatory pathways. While in a normal healthy young person, exposure to infection, cigarette smoke or injury induces oxidative stress that results in optimal activation of proteasomal pathway via Nrf2 resulting in increased NF-κB-mediated stress response that is balanced by induction of protective Nrf2 response. Notably, the UPP modification (inherent and/or environmental insult or age-related change) induces degradation of both IκB and Nrf2. The lack of compensatory antioxidant gene activation and chronic NF-κB activation, thus resulting in persistent oxidative stress and chronic inflammation. The inability to regulate protein degradation machinery and aberrant-autophagy results in fatal disease.

ARE: Antioxidant response element; HIF: Hypoxia-inducible factor; Nrf2: Nuclear factor erythroid 2-related factor 2; Ub: Ubiquitin; UPR: Ubiquitin proteasome response; VCP: Valosin containing protein; VEGF: Vascular endothelial growth factor.