Date Published: July 17, 2018
Publisher: Public Library of Science
Author(s): Hsin-Ping Chiu, Han Chiu, Chao-Fu Yang, Yi-Ling Lee, Feng-Lan Chiu, Hung-Chih Kuo, Ren-Jye Lin, Yi-Ling Lin, John W. Schoggins.
CCCH-type zinc-finger antiviral protein (ZAP) is a host factor that restricts the infection of many viruses mainly through RNA degradation, translation inhibition and innate immune responses. So far, only one flavivirus, yellow fever virus, has been reported to be ZAP-resistant. Here, we investigated the antiviral potential of human ZAP (isoform ZAP-L and ZAP-S) against three flaviviruses, Japanese encephalitis virus (JEV), dengue virus (DENV) and Zika virus (ZIKV). Infection of JEV but not DENV or ZIKV was blocked by ZAP overexpression, and depletion of endogenous ZAP enhanced JEV replication. ZAP hampered JEV translation and targeted viral RNA for 3′-5′ RNA exosome-mediated degradation. The zinc-finger motifs of ZAP were essential 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 confer sensitivity to ZAP. In summary, we identified JEV as the first ZAP-sensitive flavivirus. ZAP may act as an intrinsic antiviral factor through specific RNA binding to fight against JEV infection.
Zinc-finger CCCH-type containing, antiviral 1 (ZC3HAV1) also known as zinc-finger antiviral protein (ZAP) was first discovered in rats as a host antiviral protein against Moloney murine leukemia virus . Later, multiple RNA and DNA viruses, like retroviruses, filoviruses, alphaviruses, and hepatitis B virus were shown to display sensitivity to ZAP [2–6]. However, ZAP does not induce a universal antiviral state, since viruses such as herpes simplex virus 1 (HSV-1), vesicular stomatitis virus and yellow fever virus (YFV) are resistant to ZAP . Furthermore, viruses within the same family may exhibit different sensitivity to ZAP. For example, in the family Picornaviridae, ZAP inhibited coxsackievirus B3 but not poliovirus infection [4, 7].
ZAP exhibits antiviral activity against a variety of viruses, but flaviviruses were not known to be sensitive to ZAP until this study. Here, we demonstrate that overexpression of human ZAP (isoforms ZAP-L and ZAP-S) inhibited JEV infection and downregulation of endogenous ZAP enhanced JEV replication, indicating the intrinsic antiviral potential of ZAP. We also found that, similar to YFV , DENV and ZIKV are resistant to ZAP, supporting the notion that ZAP is not a universal antiviral factor even for viruses within the same family.