Glycobiology of syndecan-1 in bacterial infections

Abstract

Syndecan-1 (Sdc1) is a major cell surface heparan sulfate (HS) proteoglycan of epithelial cells, a cell type targeted by many bacterial pathogens early in their pathogenesis. Loss of Sdc1 in mice is a gain-of-function mutation that significantly decreases the susceptibility to several bacterial infections, suggesting that subversion of Sdc1 is an important virulence strategy. HS glycosaminoglycan (GAG) chains of cell surface Sdc1 promote bacterial pathogenesis by facilitating the attachment of bacteria to host cells. Engagement of cell surface Sdc1 HS chains by bacterial adhesins transmits signal through the highly conserved Sdc1 cytoplasmic domain, which can lead to uptake of intracellular bacterial pathogens. On the other hand, several bacteria that do not require Sdc1 for their attachment and invasion stimulate Sdc1 shedding and exploit the capacity of Sdc1 ectodomain HS GAGs to disarm innate defense mechanisms to evade immune clearance. Recent data suggest that select HS sulfate motifs, and not the overall charge of HS, are important in the inhibition of innate immune mechanisms. Here, we discuss several examples of Sdc1 subversion in bacterial infections.

Keywords: antimicrobial peptide; glycosaminoglycan; infectious disease; neutrophil; proteoglycan; syndecan.

Figure 1.. Mechanisms of subversion of Sdc1 by bacterial pathogens.

(A) Sdc1 structure: Sdc1 core protein is a type I transmembrane protein that contains an extracellular domain that harbors both (1) HS and (2) CS chains, (3) a juxtamembrane region that is cleaved by MPs during shedding, and highly conserved (4) transmembrane and (5) cytoplasmic domains. The disaccharide structure of HS is shown. (B) Sdc1 as an adhesion and internalization receptor: attachment of bacterial pathogens (e.g. N. gonorrhoeae) to cell surface Sdc1 triggers intracellular signaling that leads to bacterial internalization. (C) Sdc1 shedding: bacterial pathogens secrete virulence factors that can enhance Sdc1 shedding by activating the host cell’s MP-mediated shedding mechanism that is regulated by PTKs, Rab5, and β1 integrins (e.g. S. aureus α-toxin) or by directly cleaving Sdc1 ectodomains (e.g. S. pneumoniae ZmpC). (D) Sdc1 inhibition of innate host defense: Sdc1 ectodomains bind to and neutralize the antibacterial activity of cationic antimicrobial peptides (e.g. neutrophil-derived CRAMP).