Previous studies have found that CCCH-type zinc-finger antiviral protein (ZAP) is a host factor that restricts the infection of many viruses via RNA degradation, translation inhibition and innate immune responses. To date, only one flavivirus, yellow fever virus, has been found to be ZAP-resistant. The authors examined the antiviral potential of human ZAP (isoforms ZAP-L and ZAP-S) against three flaviviruses, Japanese encephalitis virus (JEV), dengue virus (DENV) and Zika virus (ZIKV). They found that infection of JEV, but not DENV or ZIKV, was blocked by ZAP overexpression, and depletion of endogenous ZAP enhances JEV replication. They found that ZAP hampered JEV translation and targeted viral RNA for 3′-5′ RNA exosome-mediated degradation. The zinc-finger motifs of ZAP were the essential element for RNA targeting and anti-JEV activity. JEV 3′-UTR, especially in the region with dumbbell structures and high content of CG dinucleotide, was mapped to bind ZAP and, thereby, confer sensitivity to ZAP. Therefore, JEV has been identified as the first ZAP-sensitive flavivirus, with ZAP possibly acting as an intrinsic antiviral factor through specific RNA binding to fight against JEV infection.
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