RNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions

• Published in: Nature immunology Vol. 20; no. 12; pp. 1610 - 1620
• Main Authors: Schwerk, Johannes, Soveg, Frank W., Ryan, Andrew P., Thomas, Kerri R., Hatfield, Lauren D., Ozarkar, Snehal, Forero, Adriana, Kell, Alison M., Roby, Justin A., So, Lomon, Hyde, Jennifer L., Gale, Michael, Daugherty, Matthew D., Savan, Ram
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-12-2019; Nature Publishing Group
• Subjects: 631/250/127/1212; 631/250/254; 631/250/262; 631/80/458/2133; Alphavirus Infections - genetics; Alphavirus Infections - immunology; Biological response modifiers; Biomedical and Life Sciences; Biomedicine; Feedback, Physiological; Health aspects; HEK293 Cells; Hep G2 Cells; Homeostasis; Humans; Immune clearance; Immune response; Immunity, Innate; Immunology; Infection; Infectious Diseases; Innate immunity; Interferon; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Interferons - genetics; Intracellular; Isoforms; Localization; Negative feedback; Pathogens; Protein Binding; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; Repressor Proteins - genetics; Repressor Proteins - metabolism; Ribonucleic acid; RNA; RNA - genetics; RNA - metabolism; RNA, Small Interfering - genetics; RNA-binding protein; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Sindbis Virus - physiology; Surveys; Virus diseases; Virus Replication
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-019-0527-6

The initial response to viral infection is anticipatory, with host antiviral restriction factors and pathogen sensors constantly surveying the cell to rapidly mount an antiviral response through the synthesis and downstream activity of interferons. After pathogen clearance, the host’s ability to resolve this antiviral response and return to homeostasis is critical. Here, we found that isoforms of the RNA-binding protein ZAP functioned as both a direct antiviral restriction factor and an interferon-resolution factor. The short isoform of ZAP bound to and mediated the degradation of several host interferon messenger RNAs, and thus acted as a negative feedback regulator of the interferon response. In contrast, the long isoform of ZAP had antiviral functions and did not regulate interferon. The two isoforms contained identical RNA-targeting domains, but differences in their intracellular localization modulated specificity for host versus viral RNA, which resulted in disparate effects on viral replication during the innate immune response.
Savan and colleagues show that distinct isoforms of the RNA-binding protein ZAP function as an antiviral restriction factor or as an interferon-resolution factor, based on differences in their intracellular localization.