Zinc finger protein ZFP36L1 inhibits influenza A virus through translational repression by targeting HA, M and NS RNA transcripts.

Li-Chen Yen,Ping-Cheng Liu,Shin-Ru Shih,Yu-Ling Huang,Hsin-Ping Chiu,I-Chieh Lin,Shu-Pei Lien,Li-Hsiung Lin,An-Yu Chen,Ren-Jye Lin,Chih-Heng Huang,Ching-Len Liao

doi:10.1093/nar/gkaa458

Abstract

ZFP36L1, a CCCH-type zinc finger protein, is an RNA-binding protein that participates in controlling cellular mRNA abundance and turnover by posttranscriptional regulation. Here, we demonstrated that ZFP36L1 has an important role in host defense against influenza A virus (IAV) infection. Overexpression of ZFP36L1 reduced IAV replication via translational repression of HA, M and NS RNA segment transcripts. IAV infection upregulated cellular ZFP36L1 expression, and endogenous ZFP36L1 knockdown significantly enhanced IAV replication. ZFP36L1 directly binds to IAV NS1 mRNA in the cytoplasm and blocks the expression and function of NS1 protein. Mutation of CCCH-type zinc finger domains of ZFP36L1 lost its antiviral potential and NS1 mRNA binding. Thus, ZFP36L1 can act as a host innate defense by targeting HA, M and NS mRNA transcripts to suppress viral protein translation.

Highlights

Control of posttranscriptional RNA regulation via cellular mRNA decay and translation inhibition mechanisms plays an important role in the host defense against RNA virus infection
Several of these CCCH-type zinc finger (ZF) proteins identified as RNA-binding proteins involved in host antiviral defense by diverse antiviral mechanisms are tristetraprolin (TTP) [1], monocyte chemotactic protein-induced protein-1 (MCPIP1) [2,3,4], zinc-finger antiviral protein (ZAP) [5], target of Egr1 (TOE1) [6], tetrachlorodibenzop-dioxin (TCDD)-inducible poly (ADP-ribose) polymerase (TIPARP/PARP7) [7] and long isoform of PARP12 poly(ADP-ribose) polymerase 12 (PARP12/ZC3H1) [8]
ZFP36L1 contains two CCCH-type ZF domains characterized by three Cys residues and one His residue (Figure 1A) that can directly bind to the AREs of certain mRNAs to promote mRNA deadenylation and decay [13,14,16,25]

Summary

Introduction

Control of posttranscriptional RNA regulation via cellular mRNA decay and translation inhibition mechanisms plays an important role in the host defense against RNA virus infection. Growing evidence indicates that RNA binding protein-mediated mRNA decay and translational repression machinery by CCCH-type zinc finger (ZF) proteins can function as a host innate defense against virus infection. Several of these CCCH-type ZF proteins identified as RNA-binding proteins involved in host antiviral defense by diverse antiviral mechanisms are tristetraprolin (TTP) [1], monocyte chemotactic protein-induced protein-1 (MCPIP1) [2,3,4], zinc-finger antiviral protein (ZAP) [5], target of Egr (TOE1) [6], tetrachlorodibenzop-dioxin (TCDD)-inducible poly (ADP-ribose) polymerase (TIPARP/PARP7) [7] and long isoform of PARP12 poly(ADP-ribose) polymerase 12 (PARP12/ZC3H1) [8]. TIPARP, a ZAP-like protein, binds to sindbis virus (SINV) RNA via its ZF domain and recruits an exosome to promote the degradation

Methods

Results

Conclusion