The E3 ligase TRIM56 is a host restriction factor of Zika virus and depends on its RNA-binding activity but not miRNA regulation, for antiviral function

Yang, Darong; Li, Nan L.; Wei, Dahai; Liu, Baoming; Guo, Fang; Elbahesh, Husni; Zhang, Yunzhi; Zhou, Zhi; Chen, Guo-Yun; Li, Kui

Previously, TRIM56 has been shown to possess direct antiviral activities against distinct RNA viruses, including BVDV, YFV and DENV2 from the family Flaviviridae, HCoV-OC43 from the family Coronaviridae [24, 25] , and influenza A and B viruses from the family Orthomyxoviridae [26] . However, the underlying mechanisms are unclear. It should be noted that TRIM56 is not a universally antiviral host factor against RNA viruses, as it had no inhibitory effects on several negative-stranded RNA viruses, including Sendai virus, vesicular stomatitis virus, and human metapneumovirus [25, 26] . In addition, TRIM56 was not found to impact replication of hepatitis C virus, a hepatotropic RNA virus classified in the family Flaviviridae, in permissive hepatoma Huh7 cells [25] . The present study expands the antiviral spectrum of TRIM56 to two more classical flaviviruses, ZIKV and DENV1. Mirroring the molecular determinants required for TRIM56-mediated restriction of BVDV, YFV and DENV2 [24, 25] , the E3 ligase activity and the integrity of C-terminal portion were found to be both essential for the anti-ZIKV action of TRIM56. Interestingly, the very C-terminal region is also a prerequisite for TRIM56's antiviral action against influenza viruses, although it alone was found to be sufficient in this case [26] . Notably, intracellular viral RNA replication is the molecular stage in the life cycle of all five flaviviruses at which TRIM56 targets for inhibition ( [24, 25] , and this study), arguing strongly a shared mechanism underlying the broad anti-flavivirus activity. As proposed previously [24, 25] , TRIM56 may act on shared proviral host factor(s) for post-translational modifications such as attachment of ubiquitin or ubiquitin-like modifier linkages via its E3 ligase activity, in ways that alter their turn-over rates, trafficking to and/or incorporating into viral replicase complexes. The possibility that TRIM56 binds to viral RNAs via its C-terminal region to hinder viral RNA replication was also raised [25] . As discussed below, we favor the hypothesis that these two scenarios are not mutually exclusive and they operate concurrently and/or in concert to implement viral restriction.