Novel Staphylococcal Glycosyltransferases SdgA and SdgB Mediate Immunogenicity and Protection of Virulence-Associated Cell Wall Proteins

PLoS Pathogens

Mark J. Kwakkenbos¹  Tim Beaumont¹  Arjen Q. Bakker¹  Hergen Spits¹  Tao Sai²  Andrew Sebrell²  Yana Khalfin³  Lee R. Swem⁴  Wouter L. W. Hazenbos⁴  Sophie M. Lehar⁴  Ishita M. Shah⁴  Eric J. Brown⁴  J. Hiroshi Morisaki⁴  Man-Wah Tan⁴  Sanjeev Mariathasan⁴  Kimberly K. Kajihara⁴  Satish Ramakrishnan⁴  Binh An Diep⁵  S. Jack Lin⁶  Richard Vandlen⁷  Byoung-Chul Lee⁷  Qui Phung⁸  Angela Oh⁹  Chris Koth⁹  Magnus Strandh^1,10  Klaus Koefoed^1,10  Peter S. Andersen^1,10  Min Xu^1,11  Janice Kim^1,11 

[1] AIMM Therapeutics and Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, The Netherlands;Antibody Engineering, Genentech, Inc., San Francisco, California, United States of America;Biochemical and Cellular Pharmacology, Genentech, Inc., San Francisco, California, United States of America;Dept. of Infectious Diseases, Genentech, Inc., San Francisco, California, United States of America;Division of Infectious Diseases, University of California, San Francisco, California, United States of America;Early Discovery Biochemistry, Genentech, Inc., San Francisco, California, United States of America;Protein Chemistry, Genentech, Inc., San Francisco, California, United States of America;Proteomics Lab, Genentech Inc., San Francisco, California, United States of America;Structural Biology, Genentech, Inc., San Francisco, California, United States of America;Symphogen A/S, Lyngby, Denmark;Translational Immunology, Genentech, Inc., San Francisco, California, United States of America

关键词: Staphylococcus aureus;    Staphylococcus epidermidis;    Glycosylation;    Methicillin-resistant Staphylococcus aureus;    Glycosyltransferases;    Neutrophils;    Enzyme-linked immunoassays;    Lysosomes;   

DOI  :  10.1371/journal.ppat.1003653

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY