title: Novel staphylococcal glycosyltransferases SdgA and SdgB mediate immunogenicity and protection of virulence-associated cell wall proteins.
abstract: Infection of host tissues by Staphylococcus aureus and S. epidermidis requires an unusual family of staphylococcal adhesive proteins that contain long stretches of serine-aspartate dipeptide-repeats (SDR). The prototype member of this family is clumping factor A (ClfA), a key virulence factor that mediates adhesion to host tissues by binding to extracellular matrix proteins such as fibrinogen. However, the biological siginificance of the SDR-domain and its implication for pathogenesis remain poorly understood. Here, we identified two novel bacterial glycosyltransferases, SdgA and SdgB, which modify all SDR-proteins in these two bacterial species. Genetic and biochemical data demonstrated that these two glycosyltransferases directly bind and covalently link N-acetylglucosamine (GlcNAc) moieties to the SDR-domain in a step-wise manner, with SdgB appending the sugar residues proximal to the target Ser-Asp repeats, followed by additional modification by SdgA. GlcNAc-modification of SDR-proteins by SdgB creates an immunodominant epitope for highly opsonic human antibodies, which represent up to 1% of total human IgG. Deletion of these glycosyltransferases renders SDR-proteins vulnerable to proteolysis by human neutrophil-derived cathepsin G. Thus, SdgA and SdgB glycosylate staphylococcal SDR-proteins, which protects them against host proteolytic activity, and yet generates major eptopes for the human anti-staphylococcal antibody response, which may represent an ongoing competition between host and pathogen.
authors.affiliation: Dept. of Infectious Diseases, Genentech, Inc., San Francisco, California, United States of America.
authors.forename: Wouter L W
authors.initials: WL
authors.lastname: Hazenbos
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Kajihara
authors.forename: Richard
authors.initials: R
authors.lastname: Vandlen
authors.forename: J Hiroshi
authors.initials: JH
authors.lastname: Morisaki
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Lehar
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kwakkenbos
authors.forename: Tim
authors.initials: T
authors.lastname: Beaumont
authors.forename: Arjen Q
authors.initials: AQ
authors.lastname: Bakker
authors.forename: Qui
authors.initials: Q
authors.lastname: Phung
authors.forename: Lee R
authors.initials: LR
authors.lastname: Swem
authors.forename: Satish
authors.initials: S
authors.lastname: Ramakrishnan
authors.forename: Janice
authors.initials: J
authors.lastname: Kim
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Ishita M
authors.initials: IM
authors.lastname: Shah
authors.forename: Binh An
authors.initials: BA
authors.lastname: Diep
authors.forename: Tao
authors.initials: T
authors.lastname: Sai
authors.forename: Andrew
authors.initials: A
authors.lastname: Sebrell
authors.forename: Yana
authors.initials: Y
authors.lastname: Khalfin
authors.forename: Angela
authors.initials: A
authors.lastname: Oh
authors.forename: Chris
authors.initials: C
authors.lastname: Koth
authors.forename: S Jack
authors.initials: SJ
authors.lastname: Lin
authors.forename: Byoung-Chul
authors.initials: BC
authors.lastname: Lee
authors.forename: Magnus
authors.initials: M
authors.lastname: Strandh
authors.forename: Klaus
authors.initials: K
authors.lastname: Koefoed
authors.forename: Peter S
authors.initials: PS
authors.lastname: Andersen
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
authors.forename: Man-Wah
authors.initials: MW
authors.lastname: Tan
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Mariathasan
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000235:genetics / Q000276:immunology; D001422:Bacterial Adhesion / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D056649:Cathepsin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002473:Cell Wall / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D016695:Glycosyltransferases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000502:physiology*; D051379:Mice; D020449:Repetitive Sequences, Amino Acid; D013203:Staphylococcal Infections / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D013212:Staphylococcus epidermidis / Q000502:physiology*; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D000939:Epitopes; D007074:Immunoglobulin G; D037521:Virulence Factors; D016695:Glycosyltransferases; C534094:CTSG protein, human; D056649:Cathepsin G