TY - JOUR
T1 - Novel staphylococcal glycosyltransferases SdgA and SdgB mediate immunogenicity and protection of virulence-associated cell wall proteins
AU - Hazenbos, Wouter L. W.
AU - Kajihara, Kimberly K.
AU - Vandlen, Richard
AU - Morisaki, J. Hiroshi
AU - Lehar, Sophie M.
AU - Kwakkenbos, Mark J.
AU - Beaumont, Tim
AU - Bakker, Arjen Q.
AU - Phung, Qui
AU - Swem, Lee R.
AU - Ramakrishnan, Satish
AU - Kim, Janice
AU - Xu, Min
AU - Shah, Ishita M.
AU - Diep, Binh An
AU - Sai, Tao
AU - Sebrell, Andrew
AU - Khalfin, Yana
AU - Oh, Angela
AU - Koth, Chris
AU - Lin, S. Jack
AU - Lee, Byoung-Chul
AU - Strandh, Magnus
AU - Koefoed, Klaus
AU - Andersen, Peter S.
AU - Spits, Hergen
AU - Brown, Eric J.
AU - Tan, Man-Wah
AU - Mariathasan, Sanjeev
PY - 2013
Y1 - 2013
N2 - 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
AB - 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
U2 - https://doi.org/10.1371/journal.ppat.1003653
DO - https://doi.org/10.1371/journal.ppat.1003653
M3 - Article
C2 - 24130480
SN - 1553-7366
VL - 9
SP - e1003653
JO - PLoS pathogens
JF - PLoS pathogens
IS - 10
ER -