@article{6ef9d89a4cc14f80908e7d3f4b7051ca,
title = "Viperin triggers ribosome collision-dependent translation inhibition to restrict viral replication",
abstract = "Innate immune responses induce hundreds of interferon-stimulated genes (ISGs). Viperin, a member of the radical S-adenosyl methionine (SAM) superfamily of enzymes, is the product of one such ISG that restricts the replication of a broad spectrum of viruses. Here, we report a previously unknown antiviral mechanism in which viperin activates a ribosome collision-dependent pathway that inhibits both cellular and viral RNA translation. We found that the radical SAM activity of viperin is required for translation inhibition and that this is mediated by viperin's enzymatic product, 3′-deoxy-3′,4′-didehydro-CTP (ddhCTP). Viperin triggers ribosome collisions and activates the MAPKKK ZAK pathway that in turn activates the GCN2 arm of the integrated stress response pathway to inhibit translation. The study illustrates the importance of translational repression in the antiviral response and identifies viperin as a translation regulator in innate immunity.",
keywords = "Kunjin virus, Zika virus, antiviral response, innate immunity, integrated stress response pathway, interferon-stimulated gene, ribosome collision, translational regulation, viperin",
author = "Hsu, {Jack Chun Chieh} and Maudry Laurent-Rolle and Pawlak, {Joanna B.} and Hongjie Xia and Amit Kunte and Hee, {Jia Shee} and Jaechul Lim and Harris, {Lawrence D.} and Wood, {James M.} and Evans, {Gary B.} and Shi, {Pei Yong} and Grove, {Tyler L.} and Almo, {Steven C.} and Peter Cresswell",
note = "Funding Information: We thank Dr. Yue Li for assistance in designing viperin mutants. The Cambodia Zika strain was a gift from Dr. Erol Fikrig at Yale University. Kunjin virus was a gift from Philip M. Armstrong at The Connecticut Agricultural Experiment Station. We thank Dr. Brett Lindenbach for the Brandel density gradient fractionation system. J.C.-C.H. was supported by the Cancer Research Institute Irvington Postdoctoral Fellowship, J.B.P. was supported by 5 T32 HL 7974-19 , and M.L.R. was supported by grant number KL2 TR001862 . J.L. was supported by postdoctoral fellowships from the International Human Frontier Science Program Organization ( LT000037/2018-L ) and Jane Coffin Childs Memorial Fund . This work was supported by NIH grants RO1 AI059167 (P.C.), P01 GM118303 (S.C.A.), R21-AI133329 (T.L.G. and S.C.A.), and the Price Family Foundation (S.C.A.). L.D.H., J.M.W., and G.B.E. thank the Ministry of Business Innovation & Employment for support of this work (Endeavour Fund, contract UOOX1904 [N.Z.]). We acknowledge the Albert Einstein Anaerobic Structural and Functional Genomics Resource ( http://www.nysgxrc.org/psi3/anaerobic.html ) and the W.M. Keck Foundation Biotechnology Resource Laboratory at Yale University. The Graphical Abstract is created with BioRender.com . Funding Information: We thank Dr. Yue Li for assistance in designing viperin mutants. The Cambodia Zika strain was a gift from Dr. Erol Fikrig at Yale University. Kunjin virus was a gift from Philip M. Armstrong at The Connecticut Agricultural Experiment Station. We thank Dr. Brett Lindenbach for the Brandel density gradient fractionation system. J.C.-C.H. was supported by the Cancer Research Institute Irvington Postdoctoral Fellowship, J.B.P. was supported by 5 T32 HL 7974-19, and M.L.R. was supported by grant number KL2 TR001862. J.L. was supported by postdoctoral fellowships from the International Human Frontier Science Program Organization (LT000037/2018-L) and Jane Coffin Childs Memorial Fund. This work was supported by NIH grants RO1 AI059167 (P.C.), P01 GM118303 (S.C.A.), R21-AI133329 (T.L.G. and S.C.A.), and the Price Family Foundation (S.C.A.). L.D.H. J.M.W. and G.B.E. thank the Ministry of Business Innovation & Employment for support of this work (Endeavour Fund, contract UOOX1904 [N.Z.]). We acknowledge the Albert Einstein Anaerobic Structural and Functional Genomics Resource (http://www.nysgxrc.org/psi3/anaerobic.html) and the W.M. Keck Foundation Biotechnology Resource Laboratory at Yale University. The Graphical Abstract is created with BioRender.com. J.C.-C.H. and P.C. designed the study and wrote the manuscript with input from the other authors. J.C.-C.H. M.L.R. and J.B.P. performed the experiments and analyzed the data. A.K. and J.S.H. produced iBMDM cell lines. J.L. performed analysis of RNA sequencing. H.X. and P.-Y.S. performed reporter ZIKV analysis. T.L.G. and S.C.A. performed ddhCTP detection. L.D.H. J.M.W. and G.B.E. provided ddhC. T.L.G. and S.C.A. have filed intellectual property around the use of ddhC. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = may,
day = "5",
doi = "10.1016/j.molcel.2022.02.031",
language = "English (US)",
volume = "82",
pages = "1631--1642.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "9",
}
