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Nat Immunol. 2019 Dec;20(12):1610-1620. doi: 10.1038/s41590-019-0527-6. Epub 2019 Nov 18.

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

Author information

1
Department of Immunology, School of Medicine, University of Washington, Seattle, WA, USA.
2
Section of Molecular Biology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
3
Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
4
Department of Microbiology, School of Medicine, University of Washington, Seattle, WA, USA.
5
Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA, USA.
6
Section of Molecular Biology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA. mddaugherty@ucsd.edu.
7
Department of Immunology, School of Medicine, University of Washington, Seattle, WA, USA. savanram@uw.edu.
8
Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA, USA. savanram@uw.edu.

Abstract

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.

PMID:
31740798
DOI:
10.1038/s41590-019-0527-6

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