ZC3HAV1

Zinc finger antiviral protein (ZAP) or Zinc finger CCCH-type antiviral protein 1 is a protein that in humans is encoded by the ZC3HAV1 gene.

This gene encodes a CCCH-type zinc finger protein that is thought to prevent infection by viruses by targeting viral RNA for degradation, inhibiting its translation as well as affecting programmed viral frameshifting. ZAP targets CpG rich RNA viral sequences. In addition to antiviral activities, ZAP has been reported to inhibit LINE and Alu retrotransposition.

Alternative splicing occurs at this locus and at least four isoform variants have been described with differing anti-viral activities.

While not sharing larger homologous regions, ZAP shares the uncommon CCCH zinc finger motif with tristetraprolin (TTP), which binds AU-rich elements (ARE) in RNA and promotes their degradation.

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Mechanism of ZAP mediated repression of viral gene expression: ZAP binds to ZAP responsive element(ZRE)-containing viral RNA and, along with its cofactor TRIM25, can either (a) cause RNA degradation by interacting with the putative endonuclease KHNYN or (b) repress messenger RNA translation by inhibiting eIF4A and 4G

Accessory Proteins

Multiple ZAP cofactors have been reported to be required for antiviral activity. However the E3 ubiquitin ligase TRIM25 (tripartite motif protein 25) and KHNYN (KH-like and NYN domain-containing protein) have the most well documented evidence. TRIM25 has been shown to promote ZAP activity by multimerization through its RING domain whereas KHNYN acts an active nuclease for RNA cleavage which can be partially replaced functionally by its homolog N4BP1.

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Schematic of all four ZAP isoforms and its accessory proteins TRIM25, and KHNYN, which are essential for antiviral activity

Classification of ZAP sensitive viruses

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ZAP is a potentially broad-acting antiviral factor: Different classification of viruses are both ZAP-sensitive viruses are depicted in black, while ZAP-resistant viruses are in blue