Antiviral Activity of Zinc Finger Antiviral Protein (ZAP) in Different Virus Families

Abstract

The CCCH-type zinc finger antiviral protein (ZAP) in humans, specifically isoforms ZAP-L and ZAP-S, is a crucial component of the cell's intrinsic immune response. ZAP acts as a post-transcriptional RNA restriction factor, exhibiting its activity during infections caused by retroviruses and alphaviruses. Its function involves binding to CpG (cytosine-phosphate-guanine) dinucleotide sequences present in viral RNA, thereby directing it towards degradation. Since vertebrate cells have a suppressed frequency of CpG dinucleotides, ZAP is capable of distinguishing foreign genetic elements. The expression of ZAP leads to the reduction of viral replication and impedes the assembly of new virus particles. However, the specific mechanisms underlying these effects have yet to be fully understood. Several questions regarding ZAP's mechanism of action remain unanswered, including the impact of CpG dinucleotide quantity on ZAP's activity, whether this sequence is solely required for the binding between ZAP and viral RNA, and whether the recruitment of cofactors is dependent on cell type, among others. This review aims to integrate the findings from studies that elucidate ZAP's antiviral role in various viral infections, discuss gaps that need to be filled through further studies, and shed light on new potential targets for therapeutic intervention.

Keywords: PARP-13; ZAP protein; antiviral activity.

Figure 1

Schematic image of the protein domains of the two isoforms of human ZAP: ZAP-L and ZAP-S. ZnF1–4: four CCCH-type zinc finger motifs. TPH (or TiPARP Homology domain (conserved among ZAP paralogs and containing a fifth CCCH zinc finger motif). WWE motifs. CaaX: C is cysteine, A is usually two aliphatic amino acids, and X can be a variety of amino acids.

Figure 2

TRIM25 acts as a cofactor of ZAP. ZAP binds to the CpG sequence in viral RNA and, upon sequential binding of TRIM25 and catalytic activation, induces downstream signaling to inhibit viral replication.

Figure 3

KHNYN acts as a cofactor for the antiviral activity of ZAP. KHNYN interaction with ZAP is important for the inhibition of HIV-1 containing clustered CpG dinucleotides, and this inhibition requires TRIM25.

Figure 4

System of cofactors required by ZAP to target viral RNA for degradation. DDX17 increases the efficiency of ZAP by inhibiting virus replication by targeting mRNAs for degradation via the exosome and recruitment of Dcp1:Dcp2 decapping enzyme to the 5′-end of viral RNAs, inhibiting cap-dependent mRNA translation initiation. ZAP interacts with a cellular polyadenylate-specific ribonuclease (PARN), which is a 3’-exoribonuclease that removes poly(A) tails from the 3’ end of RNAs.

Figure 5

ZAP inhibits viral mRNA translation by inhibiting the formation of eIF4F complex. ZAP, when interacting with initiation factor eIF4A, avoids viral translation by preventing the formation of the eIF4F complex (eIF4E cap-binding protein, eIF4A DEAD box RNA helicase, and eIF4G scaffolding protein). CAP: a structure found at the 5’ end of mRNA.

Figure 6

Interaction between ZAP, RIG-I, and IFN in the antiviral immune response: ZAP-S interacts with RIG-I to enhance the oligomerization and ATPase activity of RIG-I. This, in turn, increases the activation of IRF3 downstream when the RIG-I ligand, 3′pRNA, is present in human cells. DDX60 associates with RIG-I and is involved in RIG-I-dependent type I IFN production in response to viral RNA. TRIM25 activates the RIG-I pathway by facilitating K63-linked polyubiquitin chain formation through its E3 ubiquitin ligase activity. This ubiquitination promotes interaction with MAVS, leading to downstream signaling (Crosse et al., 2018 [93]; Martín-Vicente et al., 2017 [64]). DDX60 is a DEXD/H box helicase.