title: Bunyamwera virus nonstructural protein NSs counteracts interferon regulatory factor 3-mediated induction of early cell death.
abstract: The genome of Bunyamwera virus (BUN; family Bunyaviridae, genus Orthobunyavirus) consists of three segments of negative-sense RNA. The smallest segment, S, encodes two proteins, the nonstructural protein NSs, which is nonessential for viral replication and transcription, and the nucleocapsid protein N. Although a precise role in the replication cycle has yet to be attributed to NSs, it has been shown that NSs inhibits the induction of alpha/beta interferon, suggesting that it plays a part in counteracting the host antiviral defense. A defense mechanism to limit viral spread is programmed cell death by apoptosis. Here we show that a recombinant BUN that does not express NSs (BUNdelNSs) induces apoptotic cell death more rapidly than wild-type virus. Screening for apoptosis pathways revealed that the proapoptotic transcription factor interferon regulatory factor 3 (IRF-3) was activated by both wild-type BUN and BUNdelNSs infection, but only wild-type BUN was able to suppress signaling downstream of IRF-3. Studies with a BUN minireplicon system showed that active replication induced an IRF-3-dependent promoter, which was suppressed by the NSs protein. In a cell line (P2.1) defective in double-stranded RNA signaling due to low levels of IRF-3, induction of apoptosis was similar for wild-type BUN and BUNdelNSs. These data suggest that the BUN NSs protein can delay cell death in the early stages of BUN infection by inhibiting IRF-3-mediated apoptosis.
authors.affiliation: Division of Virology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G11 5JR, Scotland, United Kingdom.
authors.forename: Alain
authors.initials: A
authors.lastname: Kohl
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Clayton
authors.forename: Friedemann
authors.initials: F
authors.lastname: Weber
authors.forename: Anne
authors.initials: A
authors.lastname: Bridgen
authors.forename: Richard E
authors.initials: RE
authors.lastname: Randall
authors.forename: Richard M
authors.initials: RM
authors.lastname: Elliott
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D002042:Bunyamwera virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D002044:Bunyaviridae Infections / Q000821:virology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D050838:Interferon Regulatory Factor-3; D011401:Promoter Regions, Genetic; D012330:RNA, Double-Stranded / Q000378:metabolism; D012093:Replicon; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014779:Virus Replication
chemical_list: D017304:Annexin A5; D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C423923:NSs protein, Bunyamwera bunyavirus; D012330:RNA, Double-Stranded; D014157:Transcription Factors; D017361:Viral Nonstructural Proteins