Alternative titles; symbols
HGNC Approved Gene Symbol: ZC3HAV1
Cytogenetic location: 7q34 Genomic coordinates (GRCh38) : 7:139,043,515-139,109,720 (from NCBI)
ZC3HAV1 is a host factor that specifically inhibits replication of certain viruses by eliminating viral mRNAs in the cytoplasm. It binds directly to target viral mRNAs via its zinc finger motifs and recruits the RNA exosome to degrade the target viral mRNA (summary by Ye et al., 2010).
In their analysis of genes expressed in human fetal liver, Yu et al. (2001) identified ZC3HAV1, which they called ZAP, as a 1,524-bp cDNA (GenBank AF138863) with an open reading frame of 264 amino acids.
Gao et al. (2002) screened mammalian cDNA libraries for genes that prevent infection by a genetically marked retrovirus. Virus-resistant cells were selected from pools of transduced clones, and an active antiviral cDNA was recovered. The gene encodes a CCCH-type zinc finger protein designated ZAP for 'zinc finger antiviral protein.' Gao et al. (2002) cloned a full-length rat Zap cDNA, which contained 776 codons. Northern blot analysis of rat Zap showed that mRNA was highly expressed in kidney and liver, but undetectable in brain and testis. Two mRNAs (3.5 and 4.5 kb) were observed in most tissues, possibly corresponding to alternative splice variants.
By database searching with evolutionarily conserved sequences in the TIPARP gene (612480), Katoh and Katoh (2003) identified 2 human genes, FLJ22693 (PARP12; 612481) and ZC3HAV1, encoding deduced proteins with the same conserved domains: a WWE domain, a PARP-like domain, and a TPH domain. The N-terminal domain of the TPH domain in all 3 genes contains a CCCH-type zinc finger. Katoh and Katoh (2003) noted that PARP12 and ZCH3HAV1 share 27.5% and 26% overall amino acid sequence identity with TIPARP, respectively. They stated that the deduced ZC3HAV1 protein contains 902 amino acids.
Yu et al. (2001) assigned the ZC3HAV1 gene to chromosome 7.
Gross (2021) mapped the ZC3HAV1 gene to chromosome 7q34 based on an alignment of the ZC3HAV1 sequence (GenBank BC033105) with the genomic sequence (GRCh38).
By analysis of genomic sequences, Gao et al. (2002) mapped the mouse Zc3hav1 gene to chromosome 6.
Gao et al. (2002) found that expression of ZAP caused profound and specific loss of viral mRNAs from the cytoplasm of rat and mouse cells without affecting the levels of nuclear mRNAs. This observation suggested the existence of a previously unknown machinery for the inhibition of virus replication, targeting a step in viral gene expression.
Ye et al. (2010) reported that ZAP required DHX30 (616423) for optimal antiviral activity. Pull-down and coimmunoprecipitation assays demonstrated that human DHX30 and ZAP interacted through their N-terminal domains. Downregulation of DHX30 in 293A cells with short hairpin RNA reduced the antiviral activity of ZAP.
By yeast 2-hybrid screening and coimmunoprecipitation analysis, Ficarelli et al. (2019) found that both isoforms of human KHNYN (619579) interacted with both isoforms of human ZAP. By interacting with ZAP, KHNYN selectively decreased production of ZAP-sensitive human immunodeficiency virus (HIV)-1 (see 609423) containing clustered CpG dinucleotides in HEK293T cells in a ZAP- and TRIM25 (600453)-dependent manner. ZAP, KHNYN, and TRIM25 appeared to be in a complex together, but TRIM25 was not required for interaction between ZAP and KHNYN. KHNYN-knockout analysis in HeLa cells showed that KHNYN was required for CpG dinucleotides to inhibit infectious HIV-1 production and protein expression. KHNYN depletion also increased production of mouse leukemia virus, but not Sindbis virus, indicating that KHNYN was required for restriction of retroviral genomes. The authors concluded that KHNYN is a cofactor for ZAP to target CpG-containing retroviral RNA for degradation.
Ficarelli, M., Wilson, H., Galao, R. P., Mazzon, M., Antzin-Anduetza, I., Marsh, M., Neil, S. J. D., Swanson, C. M. KHNYN is essential for the zinc finger antiviral protein (ZAP) to restrict HIV-1 containing clustered CpG dinucleotides. eLife 8: e46767, 2019. [PubMed: 31284899] [Full Text: https://doi.org/10.7554/eLife.46767]
Gao, G., Guo, X., Goff, S. P. Inhibition of retroviral RNA production by ZAP, a CCCH-type zinc finger protein. Science 297: 1703-1706, 2002. [PubMed: 12215647] [Full Text: https://doi.org/10.1126/science.1074276]
Gross, M. B. Personal Communication. Baltimore, Md. 10/20/2021.
Katoh, M., Katoh, M. Identification and characterization of human TIPARP gene within the CCNL amplicon at human chromosome 3q25.31. Int. J. Oncol. 23: 541-547, 2003. [PubMed: 12851707]
Ye, P., Liu, S., Zhu, Y., Chen, G., Gao, G. DEXH-box protein DHX30 is required for optimal function of the zinc-finger antiviral protein. Protein Cell 1: 956-964, 2010. [PubMed: 21204022] [Full Text: https://doi.org/10.1007/s13238-010-0117-8]
Yu, Y., Zhang, C., Zhou, G., Wu, S., Qu, X., Wei, H., Xing, G., Dong, C., Zhai, Y., Wan, J., Ouyang, S., Li, L., Zhang, S., Zhou, K., Zhang, Y., Wu, C., He, F. Gene expression profiling in human fetal liver and identification of tissue- and developmental-stage-specific genes through compiled expression profiles and efficient cloning of full-length cDNAs. Genome Res. 11: 1392-1403, 2001. [PubMed: 11483580] [Full Text: https://doi.org/10.1101/gr.175501]