JOSD1 Negatively Regulates Type-I Interferon Antiviral Activity by Deubiquitinating and Stabilizing SOCS1.

The Josephin domain-containing (JOSD) protein 1 (JOSD1) is recognized as one member of deubiquitinases (DUBs) due to its catalytic "Josephin" domain. However, the in vivo deubiquitinating activity of JOSD1 remains unidentified, and the biological functions of JOSD1 are largely unknown. In this study, we report that JOSD1 plays an important role in regulating type-I interferon (IFN-I)-mediated antiviral activity. JOSD1 physically interacts with SOCS1, which is an essential negative regulator of many cytokines signaling, and enhances SOCS1 stability by deubiquitinating K48-linked polyubiquitination of SOCS1. Furthermore, JOSD1 inhibits IFN-I-induced signaling pathway and antiviral response. Interestingly, during the early stage of viral infections, the levels of JOSD1 and SOCS1 undergo downregulation, which may facilitate activation of IFN-I signaling and efficient antiviral activity. Thus, our finding identified the first deubiquitinating substrate of JOSD1 and a novel biological function of JOSD1 and may provide a potential target for IFNs-based antiviral therapy.

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