Illustration of the working hypothesis on dysregulated responses to viral infection and damage by oxidative stress in PARK7 deficiency. In healthy individuals with PARK7-sufficient cells (left), viral infection activates PPRs (MDA5/RIG-I) following sensing of viral RNA and oxidative stress signals (ROS) through stress kinases (ASK1), together inducing the production of inflammatory cytokines. Apoptosis and autophagy pathways reduce inflammation and facilitate a balanced cytokine and IFN responses to regain homeostasis. PARK7 (in green) can regulate ROS via Nrf-2 (47) and NADPH (48) (not shown) and inhibit ASK1/2 signaling pathways (49), thereby reducing inflammation. PARK7 can also modulate the activity of the specific autophagic receptor SQSTM1/p62 and contribute to the degradation of targeted proteins under oxidative stress conditions (41). In the patient with PARK7-deficient cells (right), the suppressive effect on ROS and the activating effect on autophagy are lost, resulting in enhanced inflammatory cytokine production (see Fig. 2 and Fig. 4) and reduced cellular apoptosis and autophagy (see Fig 3). Thus, PARK7 deficiency affects cellular responses during infection and cellular stress and is dominated by impaired apoptosis and autophagy, ultimately resulting in hyperinflammatory responses and pathology. NADPH, nicotinamide adenine dinucleotide phosphate; Nrf-2, nuclear factor erythroid 2-related factor 2.