Zinc finger antiviral protein (ZAP) or Zinc finger CCCH-type antiviral protein 1 is a protein that in humans is encoded by the ZC3HAV1gene.
Gene
Alternative splicing occurs at this locus and at least four isoform variants have been described with differing anti-viral activities. ZC3HAV1 has one close paralog, ZC3HAV1L that also has a winged helix domain (WHD) and zinc fingers.
Function
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.
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.
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.
Schematic of all four ZAP isoforms and its accessory proteins TRIM25, and KHNYN, which are essential for antiviral activity
Sensitive viruses
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
↑Katoh M, Katoh M (August 2003). "Identification and characterization of human TIPARP gene within the CCNL amplicon at human chromosome 3q25.31". International Journal of Oncology. 23 (2): 541–547. doi:10.3892/ijo.23.2.541. PMID12851707.
Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (October 2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nature Biotechnology. 24 (10): 1285–1292. doi:10.1038/nbt1240. PMID16964243. S2CID14294292.
