Related Articles Characterization of novel splice variants of zinc finger antiviral protein (ZAP). J Virol. 2019 May 22;: Authors: Li MMH, Aguilar EG, Michailidis E, Pabon J, Park P, Wu X, de Jong YP, Schneider WM, Molina H, Rice CM, MacDonald MR Abstract Given the unprecedented scale of the recent Ebola and Zika viral epidemics, it is crucial to understand the biology of host factors with broad antiviral action in order to develop novel therapeutic approaches. Here, we look into one such factor; zinc-finger antiviral protein (ZAP) inhibits a variety of RNA and DNA viruses. Alternative splicing results in two isoforms that differ at their C-termini; ZAPL (long), encodes a poly(ADP-ribose) polymerase (PARP)-like domain that is missing in ZAPS (short). Previously it has been shown that ZAPL is more antiviral than ZAPS while the latter is more induced by interferon (IFN). In this study, we discovered and confirmed the expression of two additional splice variants of human ZAP – ZAPXL (extra-long) and ZAPM (medium). We also found two haplotypes of human ZAP. Since ZAPL and ZAPS have differential activities, we hypothesize that all four ZAP isoforms have evolved to mediate distinct antiviral and/or cellular functions. By taking a gene knockout and reconstitution approach, we have characterized the antiviral, translational inhibition, and IFN activation activities of individual ZAP isoforms. Our work demonstrates that ZAPL and ZAPXL are more active against alphaviruses and hepatitis B virus (HBV) than ZAPS and ZAPM and elucidates the effects of splice variants on the action of a broad spectrum antiviral factor.IMPORTANCEZAP is an IFN-induced host factor that can inhibit a wide range of viruses and there is great interest in fully characterizing its antiviral mechanism. This is the first study that defines the antiviral capacity of individual ZAP isoforms in the absence of endogenous ZAP expression and hence crosstalk with other isoforms. Our data demonstrate that ZAP is expressed as four different forms – ZAPS, ZAPM, ZAPL and ZAPXL. The longer ZAP isoforms better inhibit alphaviruses and HBV while all isofoms equally inhibit Ebola virus transcription and replication. In addition, there is no difference in the ability of ZAP isoforms to enhance the induction of type I IFN expression. Our results show that the full spectrum of ZAP activities can change depending on the virus target and the relative levels of basal expression and induction by IFN or infection. PMID: 31118263 [PubMed – as supplied by publisher]

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Characterization of novel splice variants of zinc finger antiviral protein (ZAP).