title: Norovirus-Mediated Modification of the Translational Landscape via Virus and Host-Induced Cleavage of Translation Initiation Factors.
abstract: Noroviruses produce viral RNAs lacking a 5' cap structure and instead use a virus-encoded viral protein genome-linked (VPg) protein covalently linked to viral RNA to interact with translation initiation factors and drive viral protein synthesis. Norovirus infection results in the induction of the innate response leading to interferon stimulated gene (ISG) transcription. However, the translation of the induced ISG mRNAs is suppressed. A SILAC-based mass spectrometry approach was employed to analyze changes to protein abundance in both whole cell and m7GTP-enriched samples to demonstrate that diminished host mRNA translation correlates with changes to the composition of the eukaryotic initiation factor complex. The suppression of host ISG translation correlates with the activity of the viral protease (NS6) and the activation of cellular caspases leading to the establishment of an apoptotic environment. These results indicate that noroviruses exploit the differences between viral VPg-dependent and cellular cap-dependent translation in order to diminish the host response to infection.
authors.affiliation: From the ‡Division of Virology, Department of Pathology, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, UK; ee273@cam.ac.uk ig299@cam.ac.uk.
authors.forename: Edward
authors.identifier: 0000-0002-3239-8178
authors.initials: E
authors.lastname: Emmott
authors.affiliation: From the ‡Division of Virology, Department of Pathology, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, UK.
authors.forename: Frederic
authors.initials: F
authors.lastname: Sorgeloos
authors.affiliation: From the ‡Division of Virology, Department of Pathology, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Caddy
authors.affiliation: From the ‡Division of Virology, Department of Pathology, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, UK.
authors.forename: Surender
authors.initials: S
authors.lastname: Vashist
authors.affiliation: §Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Sosnovtsev
authors.affiliation: ¶Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX.
authors.forename: Richard
authors.initials: R
authors.lastname: Lloyd
authors.affiliation: ‖Proteomics facility, School of Biochemistry, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Heesom
authors.affiliation: **Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Locker
authors.affiliation: From the ‡Division of Virology, Department of Pathology, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, UK; ee273@cam.ac.uk ig299@cam.ac.uk.
authors.forename: Ian
authors.identifier: 0000-0002-9483-510X
authors.initials: I
authors.lastname: Goodfellow
mesh_terms: D017209:Apoptosis; D017250:Caliciviridae Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007553:Isotope Labeling / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods; D029322:Norovirus / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D012315:RNA Caps / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D012315:RNA Caps; D012333:RNA, Messenger; D012367:RNA, Viral; D014764:Viral Proteins