SENP6 restricts the IFN-I-induced signaling pathway and antiviral activity by deSUMOylating USP8

Abstract

Abstract Type I interferon (IFN-I) has broad-spectrum antiviral properties and is commonly used to treat viral infection in the clinic. Here, we show that SENP6 is a potent regulator of IFN-I antiviral activity. SENP6 does not affect IFN-I production induced by viruses but regulates IFN-I-activated signaling. Mechanistically, SENP6 constitutively interacts with USP8 and inhibits USP8 SUMOylation, which in turn restricts the interaction between USP8 and IFNAR2. Disassociation of USP8 with IFNAR2 enhances IFNAR2 ubiquitination and degradation, thus attenuating IFN-I antiviral activity. Consistently, downregulation of SENP6 promotes the interaction between USP8 and IFNAR2, which reduces IFNAR2 ubiquitination and therefore enhances IFN-I-induced signaling. This study deciphers a deSUMOylation-deubiquitination crosstalk that critically controls the IFN-I response to virus infection.