Deubiquitination enzyme USP35 negatively regulates MAVS signaling to inhibit anti-tumor immunity.

The RIG-I/MAVS signaling stimulates anti-tumor immunity by triggering the production of inflammatory cytokines. Activation of MAVS induced by viral RNA and RIG-I binding is critical in this pathway. However, the molecular mechanism underlying the regulation of MAVS activity and its function in anti-tumor immunity is not fully understood. Here, we report that the ubiquitin-specific protease 35 (USP35) negatively regulates the MAVS signaling. Mechanistically, USP35 interacts with MAVS and removes its K63-linked polyubiquitin chains, thereby inhibiting viral-induced MAVS-TBK1-IRF3 activation and downstream inflammatory gene expression. Importantly, depletion of USP35 significantly enhances the anti-tumor immunity and synergizes with oncolytic virotherapy to suppress xenograft tumor growth of melanoma cells. Thus, our study identifies USP35 as a negative regulator of MAVS signaling, representing a potential immunosuppressive factor in cutaneous melanoma.