title: Post-translational modification of the myxoma-virus anti-inflammatory serpin SERP-1 by a virally encoded sialyltransferase.
abstract: SERP-1 is a secreted serpin (serine-proteinase inhibitor) encoded by myxoma virus, a poxvirus pathogen of rabbits. SERP-1 is required for myxoma-virus virulence, and the purified protein has been shown to possess independent anti-inflammatory activity in animal models of restenosis and antigen-induced arthritis. As an inhibitor of serine proteinases, SERP-1 acts against tissue-type plasminogen activator, urokinase-type plasminogen activator, plasmin, thrombin and Factor Xa. In the present study, examination of SERP-1 glycosylation-site mutants showed that the N-linked glycosylation of Asn(172) was essential for SERP-1 secretion, whereas mutation of Asn(99) decreased secretion efficiency, indicating that N-linked glycosylation plays an essential role in the processing and trafficking of SERP-1. Furthermore, comparison of SERP-1 from wild-type myxoma virus and a virus containing a targeted disruption of the MST3N sialyltransferase locus demonstrated that SERP-1 is specifically modified by this myxoma-virus-encoded sialyltransferase, and is thus the first reported viral protein shown to by modified by a virally encoded glycosyltransferase. Sialylation of SERP-1 by the MST3N gene product creates a uniquely charged species of secreted SERP-1 that is distinct from SERP-1 produced from other eukaryotic expression systems, though this has no apparent effect upon the kinetics of in vitro proteinase inhibition. Rather, the role of viral sialylation of SERP-1 likely relates to masking antigenicity or targeting SERP-1 to specific sites of action in vivo.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
authors.forename: P
authors.initials: P
authors.lastname: Nash
authors.forename: M
authors.initials: M
authors.lastname: Barry
authors.forename: B T
authors.initials: BT
authors.lastname: Seet
authors.forename: K
authors.initials: K
authors.lastname: Veugelers
authors.forename: S
authors.initials: S
authors.lastname: Hota
authors.forename: J
authors.initials: J
authors.lastname: Heger
authors.forename: C
authors.initials: C
authors.lastname: Hodgkinson
authors.forename: K
authors.initials: K
authors.lastname: Graham
authors.forename: R J
authors.initials: RJ
authors.lastname: Jackson
authors.forename: G
authors.initials: G
authors.lastname: McFadden
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism*; D001216:Asparagine / Q000378:metabolism; D002460:Cell Line; D006031:Glycosylation; D006596:Hexosaminidases / Q000378:metabolism; D006801:Humans; D007525:Isoelectric Focusing; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation; D009233:Myxoma virus / Q000201:enzymology*; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D011233:Precipitin Tests; D011499:Protein Processing, Post-Translational; D015843:Serpins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012799:Sialyltransferases / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D015843:Serpins; D014764:Viral Proteins; D001216:Asparagine; D012799:Sialyltransferases; D006596:Hexosaminidases; D010959:Tissue Plasminogen Activator; D019158:N-Acetylneuraminic Acid