RNF26 Temporally Regulates Virus-Triggered Type I Interferon Induction by Two Distinct Mechanisms

Abstract

Viral infection triggers induction of type I interferons (IFNs), which are critical mediators of innate antiviral immune response. Mediator of IRF3 activation (MITA, also called STING) is an adapter essential for virus-triggered IFN induction pathways. How post-translational modifications regulate the activity of MITA is not fully elucidated. In expression screens, we identified RING finger protein 26 (RNF26), an E3 ubiquitin ligase, could mediate polyubiquitination of MITA. Interestingly, RNF26 promoted K11-linked polyubiquitination of MITA at lysine 150, a residue also targeted by RNF5 for K48-linked polyubiquitination. Further experiments indicated that RNF26 protected MITA from RNF5-mediated K48-linked polyubiquitination and degradation that was required for quick and efficient type I IFN and proinflammatory cytokine induction after viral infection. On the other hand, RNF26 was required to limit excessive type I IFN response but not proinflammatory cytokine induction by promoting autophagic degradation of IRF3. Consistently, knockdown of RNF26 inhibited the expression of IFNB1 gene in various cells at the early phase and promoted it at the late phase of viral infection, respectively. Furthermore, knockdown of RNF26 inhibited viral replication, indicating that RNF26 antagonizes cellular antiviral response. Our findings thus suggest that RNF26 temporally regulates innate antiviral response by two distinct mechanisms.

Author Summary

Virus infection induces the host cells to produce type I interferons, which are secreted proteins important for the host to clear viruses. Previously, we identified a cellular protein called MITA, which is essential for virus-triggered induction of interferons. In this study, we found an enzyme called RNF26 could covalently modify MITA with one type of polypeptide, called polyubiquitin. This modification caused increased stability of MITA after viral infection. RNF26 also caused disability of IRF3, another important component required for virus-triggered interferon induction. Thus, RNF26 could temporally regulate virus-triggered interferon induction by two distinct mechanisms. This discovery helps to understand how the antiviral response is delicately regulated.