Open AccessRNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions
Author(s) -
Johannes Schwerk,
Frank Soveg,
Andrew P Ryan,
Kerri R. Thomas,
Lauren D. Hatfield,
Snehal Ozarkar,
Adriana Forero,
Alison Kell,
Justin A. Roby,
Lomon So,
Jennifer Hyde,
Michael Gale,
Matthew D. Daugherty,
Ram Savan
Publication year - 2019
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-019-0527-6
Subject(s) - interferon , biology , antiviral protein , rna , gene isoform , innate immune system , viral replication , immune system , microbiology and biotechnology , interferon regulatory factors , messenger rna , virology , virus , immunology , genetics , gene
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.