Abstract
Abstract Type-I Interferons (IFN-I), which are innate immune cytokines with broad-spectrum antiviral effects, are regulated by the host Ubiquitin (Ub) system. Evidence has shown that new forms of poly-Ub chains, which are not covalently attached to any protein (termed unanchored poly-Ub), are important activators of kinase activity in vitro. We recently reported that unanchored K48-linked poly-Ub synthesized by the E3-Ub ligase TRIM6 promote IFN-mediated antiviral innate immunity in vivo by activating the IKKɛ kinase. Intriguingly, we found that two different highly pathogenic viruses, Nipah (NiV; Paramyxoviridae family) and Ebola (EBOV; Filoviridae family), hijack TRIM6 to promote virus replication through mechanisms that involve both covalent and unanchored Ub. This indicates that host antiviral factors can have direct pro-viral functions. We also found that Zika virus (ZIKV; Flaviviridae family), which can cause congenital microcephaly in newborns, requires ubiquitination of viral proteins for efficient replication. Importantly, ZIKV ubiquitination occurs in vivo in a tissue-specific manner. Recombinant infectious ZIKV mutants that lack ubiquitination on specific sites are attenuated in mice and appear to differentially replicate in tissues. As compared to other flaviviruses, ZIKV acquired an additional ubiquitination site, which may be responsible for providing ZIKV an advantage to replicate in brain and reproductive tissue. This would be the first example of a flavivirus utilizing the Ub system for tissue tropism. Taken together, our work suggests that divergent viruses hijack similar innate immune host factors to enhance their replication. This information could help design novel broad-spectrum antiviral strategies
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