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J. Biol. Chem., Vol. 282, Issue 1, 159-167, January 5, 2007

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Streptococcus pneumoniae Sheds Syndecan-1 Ectodomains through ZmpC, a Metalloproteinase Virulence Factor^*

Ye Chen, Atsuko Hayashida, Allison E. Bennett, Susan K. Hollingshead, and Pyong Woo Park^¶||1

From the Departments of Medicine, ^¶Molecular and Cellular Biology, and ^||Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030 and the Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294

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.

Received for publication, September 5, 2006 , and in revised form, November 10, 2006.

^* This work was supported by National Institutes of Health Grants HL69050 and HL73725 and an American Lung Association Career Investigator Award (to P. W. P.) and National Institutes of Health Grants AI053749 and T32AI07041 (to S. K. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Section of Infectious Diseases, Baylor College of Medicine, One Baylor Plaza, Rm. N1319, Houston, TX 77030. Tel.: 713-798-4504; Fax: 713-798-8948; E-mail: pwpark{at}bcm.tmc.edu.

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