title: Mutations in modified virus Ankara protein 183 render it a non-functional counterpart of B14, an inhibitor of nuclear factor kappaB activation.
abstract: Vaccinia virus (VACV) encodes multiple proteins to evade host innate immunity, including B14, a virulence factor that binds to the inhibitor of kappaB kinase beta (IKKbeta) and blocks nuclear factor kappaB (NF-kappaB) activation. B14 shares 95 % amino acid identity with the 183 protein encoded by modified virus Ankara (MVA), an attenuated VACV strain being developed as a vaccine vector. To evaluate whether the immunogenicity of MVA might be increased by manipulation of MVA immunomodulatory proteins, the MVA counterpart of B14, protein 183, was characterized. Unlike B14, protein 183 was unstable in eukaryotic cells unless proteasome-mediated protein degradation was inhibited. Furthermore, 183 did not inhibit NF-kappaB activation in response to cytokine stimulation, and did not restore the virulence of VACV strain Western Reserve lacking gene B14R. The instability and non-functionality of 183 are probably explained by a deletion of 6 aa within alpha-helix 6 of the B14 crystal structure.
authors.affiliation: Department of Virology, Imperial College London, London W2 1PG, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: McCoy
authors.forename: Aodhnait S
authors.initials: AS
authors.lastname: Fahy
authors.forename: Ron A-J
authors.initials: RA
authors.lastname: Chen
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Smith
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D005814:Genes, Viral; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology / Q000502:physiology*; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology; D014774:Virulence / Q000235:genetics / Q000276:immunology
chemical_list: D050505:Mutant Proteins; D016328:NF-kappa B; D014764:Viral Proteins; D014765:Viral Vaccines
references.citation: J Gen Virol. 2005 Jul;86(Pt 7):1997-2006
references.pmid: 15958679
references.citation: PLoS Pathog. 2008 Feb 8;4(2):e22
references.pmid: 18266467
references.citation: J Gen Virol. 2007 Dec;88(Pt 12):3249-3259
references.pmid: 18024893
references.citation: J Virol. 2009 Mar;83(6):2469-79
references.pmid: 19129442
references.citation: J Gen Virol. 1999 Oct;80 ( Pt 10):2751-2755
references.pmid: 10573171
references.citation: J Biol Chem. 1991 Oct 25;266(30):20103-9
references.pmid: 1657913
references.citation: J Gen Virol. 2006 Jun;87(Pt 6):1451-1458
references.pmid: 16690909
references.citation: N Engl J Med. 1969 Nov 27;281(22):1201-8
references.pmid: 4186802
references.citation: J Gen Virol. 2006 Jan;87(Pt 1):29-38
references.pmid: 16361415
references.citation: J Gen Virol. 1991 May;72 ( Pt 5):1031-8
references.pmid: 2033387
references.citation: Zentralbl Bakteriol Orig. 1964 Dec;195(1):24-35
references.pmid: 5890664
references.citation: Virology. 1998 May 10;244(2):365-96
references.pmid: 9601507
references.citation: Zentralbl Bakteriol B. 1978 Dec;167(5-6):375-90
references.pmid: 219640
references.citation: Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10847-51
references.pmid: 1438287
references.citation: PLoS Pathog. 2008 Aug 15;4(8):e1000128
references.pmid: 18704168
references.citation: J Gen Virol. 1998 May;79 ( Pt 5):1159-67
references.pmid: 9603331
references.citation: Dtsch Med Wochenschr. 1974 Nov 22;99(47):2386-92
references.pmid: 4426258
references.citation: J Gen Virol. 2002 Aug;83(Pt 8):1977-1986
references.pmid: 12124461
references.citation: Berl Munch Tierarztl Wochenschr. 1994 Aug;107(8):253-6
references.pmid: 7945180
references.citation: Virology. 1994 Oct;204(1):376-90
references.pmid: 8091668
references.citation: J Virol. 1990 Jun;64(6):3108-11
references.pmid: 2159565
references.citation: Nature. 1983 Apr 7;302(5908):490-5
references.pmid: 6835382
references.citation: Virology. 2001 Sep 15;288(1):175-87
references.pmid: 11543670