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J. Biol. Chem., Vol. 281, Issue 20, 14215-14223, May 19, 2006

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Multifunctional Glyceraldehyde-3-phosphate Dehydrogenase of Streptococcus pyogenes Is Essential for Evasion from Neutrophils^*

Yutaka Terao, Masaya Yamaguchi, Shigeyuki Hamada, and Shigetada Kawabata¹

From the Department of Oral and Molecular Microbiology, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan and the Department of Life Science, Nihon University Advanced Research Institute for the Sciences and Humanities, Chiyodaku, Tokyo 102-8251, Japan

Streptococcus pyogenes is an important pathogen that causes pharyngitis, sepsis, and rheumatic fever. Cell-associated streptococcal C5a peptidase (ScpA) protects S. pyogenes from phagocytosis and has been suggested to interrupt host defenses by enzymatically cleaving complement C5a, a major factor in the accumulation of neutrophils at sites of infection. How S. pyogenes recognizes and binds to C5a, however, is unclear. We detected a C5a-binding protein in 8 M urea extracts of S. pyogenes by ligand blotting using biotinylated C5a. Searching of genome databases showed that the C5a-binding protein is identical to the streptococcal plasmin receptor (Plr), also known as streptococcal surface dehydrogenase (SDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In the present study we identified a novel function of this multifunctional protein. Western blotting and immunofluorescence microscopy with anti-Plr/SDH/GAPDH showed that Plr/SDH/GAPDH is located on the bacterial surface and released into the culture supernatant. Next, we examined whether the streptococcal Plr/SDH/GAPDH inhibits the biological effects of C5a on human neutrophils. We found that soluble Plr/SDH/GAPDH inhibits C5a-activated chemotaxis and H₂O₂ production. Furthermore, our results suggested that soluble Plr/SDH/GAPDH captures C5a, inhibiting its chemotactic function. Also, cell-associated Plr/SDH/GAPDH and ScpA were both necessary for the cleavage of C5a on the bacterial surface. Together, these results indicate that the multifunctional protein Plr/SDH/GAPDH has additional functions that help S. pyogenes escape detection by the host immune system.

Received for publication, December 16, 2005 , and in revised form, March 23, 2006.

^* This research was supported in part by a Grant from the 21st century Center of Excellence program, grants-in-aid for Scientific Research on Priority Areas and Young Scientists (B) from the Ministry of Education, Culture, Sports, Science, and Technology, a grant from PRESTO, Japan Science and Technology Agency, grants-in-aid for Scientific Research (B) from the Japan Society for the Promotion of Science, and the Research Grant for Longevity Sciences (17C-5) from the Ministry of Health, Labour, and Welfare. 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. Tel.: 81-6-6879-2898; Fax: 81-6-6878-4755; E-mail: kawabata{at}dent.osaka-u.ac.jp.

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