title: Streptococcus pneumoniae sheds syndecan-1 ectodomains through ZmpC, a metalloproteinase virulence factor.
abstract: Several microbial pathogens stimulate the ectodomain shedding of host cell surface proteins to promote their pathogenesis. We reported previously that Pseudomonas aeruginosa and Staphylococcus aureus activate the ectodomain shedding of syndecan-1 and that syndecan-1 shedding promotes P. aeruginosa pathogenesis in mouse models of lung and burned skin infections. However, it remains to be determined whether activation of syndecan-1 shedding is a virulence mechanism broadly used by pathogens. Here we show that Streptococcus pneumoniae stimulates syndecan-1 shedding in cell culture-based assays. S. pneumoniae-induced syndecan-1 shedding was repressed by peptide hydroxamate inhibitors of metalloproteinases but not by inhibitors of intracellular signaling pathways previously found to be essential for syndecan-1 shedding caused by P. aeruginosa, S. aureus, or other shedding agonists. A 170-kDa protein fraction with a peptide hydroxamate-sensitive shedding activity was purified by ammonium sulfate precipitation, DEAE chromatography, and size exclusion chromatography. Mass spectrometry analyses revealed that the 170-kDa fraction is composed of ZmpB and ZmpC, two metalloproteinase virulence factors of S. pneumoniae. Both the purified 170-kDa ZmpB/ZmpC fraction and unfractionated S. pneumoniae culture supernatant generated syndecan-1 ectodomains that are smaller than those released by endogenous shedding. Further, a mutant S. pneumoniae strain deficient in zmpC, but not zmpB, lost its capacity to stimulate syndecan-1 shedding. These data demonstrate that S. pneumoniae directly sheds syndecan-1 ectodomains through the action of ZmpC.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hayashida
authors.forename: Allison E
authors.initials: AE
authors.lastname: Bennett
authors.forename: Susan K
authors.initials: SK
authors.lastname: Hollingshead
authors.forename: Pyong Woo
authors.initials: PW
authors.lastname: Park
mesh_terms: D000818:Animals; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004742:Enhancer Elements, Genetic; D017353:Gene Deletion; D013058:Mass Spectrometry; D008666:Metalloendopeptidases / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D017434:Protein Structure, Tertiary; D012756:Sheep; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000378:metabolism*; D053668:Syndecan-1 / Q000378:metabolism*; D037521:Virulence Factors / Q000737:chemistry*
chemical_list: D017931:DNA Primers; D053668:Syndecan-1; D037521:Virulence Factors; C412019:ZmpB enzyme; D008666:Metalloendopeptidases; C478168:ZmpC protein, Streptococcus pneumoniae