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.^[5][6][7]

ZC3HAV1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2X5Y, 4X52
Identifiers
Aliases	ZC3HAV1, ARTD13, FLB6421, PARP13, ZAP, ZC3H2, ZC3HDC2, zinc finger CCCH-type containing, antiviral 1
External IDs	OMIM: 607312; MGI: 1926031; HomoloGene: 10585; GeneCards: ZC3HAV1; OMA:ZC3HAV1 - orthologs
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q34 Start 139,043,515 bp[1] End 139,132,122 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 B1|6 17.72 cM Start 38,282,221 bp[2] End 38,331,538 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in trabecular bone endothelial cell visceral pleura blood Epithelium of choroid plexus parietal pleura jejunal mucosa pancreatic ductal cell superficial temporal artery bronchial epithelial cell Top expressed in Paneth cell endothelial cell of lymphatic vessel mesenteric lymph nodes blood granulocyte cumulus cell transitional epithelium of urinary bladder spleen hair follicle bone marrow More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding protein binding RNA binding cadherin binding NAD+ ADP-ribosyltransferase activity NAD+ binding protein ADP-ribosylase activity Cellular component cytoplasm nucleus cytosol Biological process positive regulation of interferon-alpha production immune system process response to virus positive regulation of mRNA catabolic process negative regulation of viral genome replication positive regulation of RIG-I signaling pathway defense response to virus positive regulation of I-kappaB kinase/NF-kappaB signaling innate immune response positive regulation of interferon-beta production protein poly-ADP-ribosylation protein ADP-ribosylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 56829 78781 Ensembl ENSG00000105939 ENSMUSG00000029826 UniProt Q7Z2W4 Q3UPF5 RefSeq (mRNA) NM_020119 NM_024625 NM_001363491 NM_028421 NM_028864 NM_001347122 RefSeq (protein) NP_064504 NP_078901 NP_001350420 NP_001334051 NP_082697 NP_083140 Location (UCSC) Chr 7: 139.04 – 139.13 Mb Chr 6: 38.28 – 38.33 Mb PubMed search [3] [4]
Wikidata
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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.^[8][9][10] ZAP targets CpG rich RNA viral sequences.^[11] In addition to antiviral activities, ZAP has been reported to inhibit LINE and Alu retrotransposition.^[12]

Alternative splicing occurs at this locus and at least four isoform variants have been described with differing anti-viral activities.^[7][8]

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.^[13]

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.^[14][15][16] 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.^[17]

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

Classification of ZAP 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