The broad-spectrum antiviral functions of IFIT and IFITM proteins

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Key Points

IFN-induced protein with tetratricopeptide repeats (IFIT) proteins — which are induced after type I interferon (IFN)- or IFN-regulatory factor 3 (IRF3)-dependent signalling — contribute to antiviral defence against some viruses by binding to components of the eukaryotic initiation factor 3 (eIF3) translation initiation complex and inhibiting protein translation.
Mutant flaviviruses, poxviruses and coronaviruses lacking 2′- O methyltransferase enzymes are attenuated in wild-type primary cells and mice but pathogenic in the absence of IFIT1 expression. Thus, IFIT proteins restrict viruses lacking 2′- O methylation of the 5′ RNA cap.
IFIT proteins form a multiprotein complex to bind viral RNA displaying a 5′-ppp motif. By sequestering viral RNA containing 5′-ppp, IFIT proteins function as both a pathogen sensor and an effector molecule.
IFN-induced transmembrane protein (IFITM) proteins constitute a family of small IFN-inducible proteins. Unlike IFIT proteins, IFITM proteins have two transmembrane domains and block the replication of enveloped viruses, including influenza A virus, dengue virus, Ebola virus and SARS coronavirus, at a step before these viruses enter the cytosol.
IFITM proteins seem to be specialized in their activity. IFITM3 makes the primary contribution to the control of influenza A virus in mice and probably humans, whereas other human and mouse IFITM proteins more efficiently restrict infection by Ebola virus and SARS coronavirus.
The mechanisms by which IFITM proteins prevent the entry of enveloped viruses remain unclear, but they probably involve alterations in the properties or the trafficking of intracellular compartments where these viruses traverse cellular membranes.

Abstract

Recent interest in identifying interferon-stimulated genes that have activity against a wide range of viruses has advanced our understanding of the IFIT and IFITM families and shown the many mechanisms by which host factors can restrict viral replication.

Abstract

Over the past few years, several groups have identified new genes that are transcriptionally induced downstream of type I interferon (IFN) signalling and that inhibit infection by individual or multiple families of viruses. Among these IFN-stimulated genes with antiviral activity are two genetically and functionally distinct families — the IFN-induced protein with tetratricopeptide repeats (IFIT) family and the IFN-induced transmembrane protein (IFITM) family. This Review focuses on recent advances in identifying the unique mechanisms of action of IFIT and IFITM proteins, which explain their broad-spectrum activity against the replication, spread and pathogenesis of a range of human viruses.

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The type I interferon (IFN) response protects cells from invading viral pathogens. The cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery over 25 years ago 1,2,3 , only few have been characterized with respect to antiviral activity. For most, little is known about their antiviral potential, their target specificity, and their mechanisms of action. Using an overexpression screening approach, we show that different viruses are targeted by unique sets of ISGs, with each viral species susceptible to multiple antiviral genes with a range of inhibitory activities. To conduct the screen, over 380 ISGs were tested for their ability to inhibit the replication of several important viruses including hepatitis C virus (HCV), yellow fever virus (YFV), West Nile virus (WNV), chikungunya virus (CHIKV), Venezuelan equine encephalitis virus (VEEV), and human immunodeficiency virus (HIV-1). Broadly acting effectors included IRF1, C6orf150, HPSE, RIG-I, MDA5, and IFITM3, while more targeted antiviral specificity was observed with DDX60, IFI44L, IFI6, IFITM2, MAP3K14, MOV10, NAMPT, OASL, RTP4, TREX1, and UNC84B. Combined expression of two-ISG pairs showed additive antiviral effects similar to moderate IFN doses. Mechanistic studies revealed a common theme of translational inhibition for numerous effectors. Several ISGs, including ADAR, FAM46C, LY6E, and MCOLN2, enhanced replication of certain viruses, highlighting another layer of complexity in the highly pleiotropic IFN system.

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Author and article information

Contributors

Michael S. Diamond: diamond@borcim.wustl.edu

Bio :

Michael S. Diamond received his M.D. and Ph.D. from Harvard University, Cambridge, Massachusetts, USA, and his postdoctoral and clinical training in infectious diseases and virology from the University of California, Berkeley, USA, and the University of California, San Francisco, USA. He is currently a professor of medicine, molecular microbiology, pathology and immunology at Washington University School of Medicine, St. Louis, Missouri, USA, and the Co-Director of the Midwest Regional Center for Excellence in Biodefense and Emerging Infectious Disease Research, St. Louis, Missouri, USA. Michael Diamond's research focuses on the interface between viral pathogenesis and the host immune response. More recently, his group has studied how novel effector molecules of the innate immune response restrict infection by multiple families of pathogenic human viruses.

Michael Farzan: farzan@hms.harvard.edu

Bio :

Michael Farzan received his A.B. and Ph.D. degrees and his postdoctoral training from Harvard University. He is currently a professor of microbiology and immunobiology at Harvard Medical School. Michael Farzan's research focuses on the entry processes of enveloped viruses, how innate and adaptive immune responses control these processes, and how these immune responses can be emulated or amplified to prevent or control viral infections.

Journal

Journal ID (nlm-ta): Nat Rev Immunol

Journal ID (iso-abbrev): Nat. Rev. Immunol

Title: Nature Reviews. Immunology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1474-1733

ISSN (Electronic): 1474-1741

Publication date (Electronic): 14 December 2012

Publication date (Print): 2013

Volume: 13

Issue: 1

Pages: 46-57

Affiliations

[1 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Departments of Medicine, , Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, ; 660 South Euclid Avenue, St Louis, 63110 Missouri USA

[2 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Microbiology and Immunobiology, , and the New England Primate Research Center, Harvard Medical School, ; 1 Pine Hill Drive, Southborough, 01772 Massachusetts USA

Article

Publisher ID: BFnri3344

DOI: 10.1038/nri3344

PMC ID: 3773942

PubMed ID: 23237964

SO-VID: 997b6615-e682-415e-8dd6-3644650d3d82

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.