Superoxide dismutase 2 (SOD2) is essential in radical scavenging, which balances the intracellular level of reactive oxygen species (ROS). The dysfunction of SOD2 is associated with increasing incidence of various human diseases, including cancer, neuron diseases, and myocardial defects. However, the connections between SOD2-mediated oxidative homeostasis and innate immune response remain unclear. In this study, we report that SOD2 is a crucial regulator of antiviral signaling. Depletion of SOD2 impairs RNA virus-induced type I interferon (IFN) and proinflammatory cytokine production, resulting in enhanced viral replication. Type I IFN production is highly sensitive to cellular level of ROS. SOD2 deficiency-mediated ROS accumulation potently inhibits RIG-I-like receptor (RLR)-induced innate immune responses through the regulation of nuclear factor-kappa B (NF-κB) and interferon regulatory factor-3 activation. These findings uncover a novel role for SOD2 in regulating RLR-mediated antiviral innate immune signaling.

Dengue virus (DENV) is a mosquito-borne single-stranded RNA virus causing human disease with variable severity. The production of massive inflammatory cytokines in dengue patients has been associated with dengue disease severity. However, the regulation of these inflammatory responses remains unclear. In this study, we report that SIRT6 is a negative regulator of innate immune responses during DENV infection. Silencing of Sirt6 enhances DENV-induced proinflammatory cytokine and chemokine production. Overexpression of SIRT6 inhibits RIG-I-like receptor (RLR) and Toll-like receptor 3 (TLR3) mediated NF-κB activation. The sirtuin core domain of SIRT6 is required for the inhibition of NF-κB p65 function. SIRT6 interacts with the DNA binding domain of p65 and competes with p65 to occupy the Il6 promoter during DENV infection. Collectively, our study demonstrates that SIRT6 negatively regulates DENV-induced inflammatory response via RLR and TLR3 signaling pathways.

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