Large Yellow Croaker ( Larimichthys Crocea ) Mitofusin 2 Inhibits Type I IFN Responses by Degrading MAVS Via Enhanced K48-linked Ubiquitination

In mammals, mitofusin 2 (MFN2) is involved in mitochondrial fusion, and suppresses the virus-induced RIG-I-like receptor (RLR) signaling pathway. However, little is known about the function of MFN2 in non-mammalian species. In the present study, we cloned an MFN2 ortholog ( Lc MFN2) in large yellow croaker ( Larimichthys crocea ). Phylogenetic analysis showed that MFN2 emerged after the divergence of amphioxus and vertebrates. The protein sequences of MFN2 were well conserved from fish to mammals. Lc MFN2 was expressed in all the tissues/organs examined at different levels, and its expression was upregulated in response to poly(I:C) stimulation. Overexpression of Lc MFN2 inhibited MAVS-induced type I interferon (IFN) promoter activation and antiviral gene expression. In contrast, knockdown of endogenous Lc MFN2 enhanced poly(I:C) induced production of type I IFNs. Additionally, Lc MFN2 enhanced K48-linked polyubiquitination of MAVS, promoting its degradation. Also, overexpression of Lc MFN2 impaired the cellular antiviral response, as evidenced by the increased expression of viral genes and more severe cytopathic effects (CPE) in cells infected with spring viremia of carp virus (SVCV). These results indicated that Lc MFN2 inhibited type I IFN response by degrading MAVS, suggesting its negative regulatory role in cellular antiviral response. Therefore, our study sheds a new light on the regulatory mechanisms of the cellular antiviral response in teleosts.