Enterovirus 71 antagonizes the inhibition of the host intrinsic antiviral factor A3G

Zhaolong Li,Wenwen Zheng,Yue Liu,Xin Liu,Xiao-Fang Yu,Shanshan Ning,Hong Wang,Xing Su,Baisong Zheng,Wenyan Zhang

doi:10.1093/nar/gky840

Zhaolong Li, Wenwen Zheng + Show 8 more

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https://doi.org/10.1093/nar/gky840

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Abstract

Although the host restriction factor APOBEC3G (A3G) has broad spectrum antiviral activity, whether A3G inhibits enterovirus 71 (EV71) has been unclear until now. In this study, we demonstrated for the first time that A3G could inhibit EV71 virus replication. Silencing A3G in H9 cells enhanced EV71 replication, and EV71 replication was lower in H9 cells expressing A3G than in Jurkat cells without A3G expression, indicating that the EV71 inhibition was A3G-specific. Further investigation revealed that A3G inhibited the 5′UTR activity of EV71 by competitively binding to the 5′UTR through its nucleic acid binding activity. This binding impaired the interaction between the 5′UTR and the host protein poly(C)-binding protein 1 (PCBP1), which is required for the synthesis of EV71 viral proteins and RNA. On the other hand, we found that EV71 overcame A3G suppression through its non-structural protein 2C, which induced A3G degradation through the autophagy–lysosome pathway. Our research provides new insights into the interplay mechanisms of A3G and single-stranded positive RNA viruses.

Highlights

Enterovirus 71 (EV71), a member of the enterovirus A species of the Picornaviridae family, causes hand, foot and mouth disease (HFMD), which has become a severe public health problem causing both economic and social panic
We observed that the expression of A3G was reduced with EV71 replication, especially at 72 h (Figure 1A, lanes 11 and 12 compared to 2 and 3), which was consistent with the phenomenon that viral VP1 protein and viral RNA levels were restored at 72 h, indicating that EV71 may have developed strategies to antagonize A3G restriction
Unlike the requirement that A3G be incorporated into virions to inhibit the Vifdeficient HIV-1 virus [45,46], we did not observe that A3G was packaged into EV71 virions (Figure 1A, lower panel)

Summary

Introduction

Enterovirus 71 (EV71), a member of the enterovirus A species of the Picornaviridae family, causes hand, foot and mouth disease (HFMD), which has become a severe public health problem causing both economic and social panic. EV71, which was first recognized in California in 1969 [4], is a single-stranded positive RNA virus that has approximately 7410 nucleotides with a single open reading frame (ORF) encoding a polyprotein flanked by untranslated regions (UTR) at its 5 and 3 ends [5]. Previous studies demonstrated that host proteins, such as hnRNP A1, hnRNP K and protein poly(C)-binding protein 1 (PCBP1), could interact with the 5 UTR of picornaviruses and promote viral protein translation and virus replication [8,9,10,11,12,13]. The P1 region encodes the capsid, which comprises four structural proteins: VP1, VP2, VP3 and VP4. The P2 and P3 regions encode the non-structural proteins, including 2A, 2B, 2C, 3A, 3B, 3C and 3D [14]

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