Inhibition of Japanese encephalitis virus infection by the host zinc-finger antiviral protein.

Yi-Ling Lin,Yi-Ling Lee,Hsin-Ping Chiu,Chao-Fu Yang,Han Chiu,Hung-Chih Kuo,Ren-Jye Lin,Feng-Lan Chiu,John W Schoggins

doi:10.1371/journal.ppat.1007166

Abstract

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.

Highlights

Zinc-finger CCCH-type containing, antiviral 1 (ZC3HAV1) known as zinc-finger antiviral protein (ZAP) was first discovered in rats as a host antiviral protein against Moloney murine leukemia virus [1]
We tested the antiviral potential of ZAP against three flaviviruses and found that Japanese encephalitis virus (JEV) was ZAP-sensitive, while dengue virus and Zika virus were ZAP-resistant
Our findings highlight the ZAP-mediated antiJEV mechanisms and extend the antiviral spectrum of ZAP to include a member of the Flavivirus genus

Summary

Introduction

Zinc-finger CCCH-type containing, antiviral 1 (ZC3HAV1) known as zinc-finger antiviral protein (ZAP) was first discovered in rats as a host antiviral protein against Moloney murine leukemia virus [1]. Viruses within the same family may exhibit different sensitivity to ZAP. ZAP exhibits antiviral activity generally via posttranscriptional RNA regulation, such as mRNA decay and translation inhibition. ZAP recruits the RNA processing exosome complex and poly(A)-specific ribonuclease (PARN) to degrade the target RNA from the 30-end [6, 10]. ZAP interacts with p72 RNA helicase to recruit decapping enzymes DCP1/DCP2 and exoribonuclease XRN1 to degrade the target RNA from the 50-end [6, 11]. Besides targeting RNA accumulation, ZAP can block translation of incoming viral RNA of Sindbis virus (SINV) [4] probably by interrupting the interaction between translational initiation factors eIF4A and eIF4G [12]. ZAP-S can associate with retinoic acid-inducible gene I (RIG-I), a key sensor to recognize viral RNA, to promote the innate immune response and contribute to its antiviral potential [13]

Methods

Results

Discussion

Conclusion