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J. Biol. Chem., Vol. 281, Issue 50, 38668-38674, December 15, 2006

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Chondroitin 4-O-Sulfotransferase-1 Regulates E Disaccharide Expression of Chondroitin Sulfate Required for Herpes Simplex Virus Infectivity^*

Toru Uyama¹, Miho Ishida, Tomomi Izumikawa, Edward Trybala, Frank Tufaro^¶, Tomas Bergström, Kazuyuki Sugahara², and Hiroshi Kitagawa³

From the Department of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan, the Department of Clinical Virology, Göteborg University, Guldhedsgatan 10B, S-413 46 Göteborg, Sweden, and ^¶Allera Health Products, Inc., St. Petersburg, Florida 33701

We have demonstrated a defect in expression of chondroitin 4-O-sulfotransferase-1 (C4ST-1) in murine sog9 cells, which are poorly sensitive to infection by herpes simplex virus type 1 (HSV-1). Sog9 cells were previously isolated as CS-deficient cells from gro2C cells, which were partially resistant to HSV-1 infection and defective in the expression of heparan sulfate (HS) because of a splice site mutation in the EXT1 gene encoding the HS-synthesizing enzyme. Here we detected a small amount of CS chains in sog9 cells with a drastic decrease in 4-O-sulfation compared with the parental gro2C cells. RT-PCR revealed that sog9 cells had a defect in the expression of C4ST-1 in addition to EXT1. Gel filtration analysis showed that the decrease in the amount of CS in sog9 cells was the result of a reduction in the length of CS chains. Transfer of C4ST-1 cDNA into sog9 cells (sog9-C4ST-1) restored 4-O-sulfation and amount of CS, verifying that sog9 cells had a specific defect in C4ST-1. Furthermore, the expression of C4ST-1 rendered sog9 cells significantly more susceptible to HSV-1 infection, suggesting that CS modified by C4ST-1 is sufficient for the binding and infectivity of HSV-1. Analysis of CS chains of gro2C and sog9-C4ST-1 cells revealed a considerable proportion of the E disaccharide unit, consistent with our recent finding that this unit is an essential component of the HSV receptor. These results suggest that C4ST-1 regulates the expression of the E disaccharide unit and the length of CS chains, the features that facilitate infection of cells by HSV-1.

Received for publication, October 2, 2006

^* This work was supported in part by Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology (JST) Corporation (to H. K. and K. S.), the Science Research Promotion Fund of the Japan Private School Promotion Foundation, and Grants-in-Aid for Scientific Research 16390026 (to K. S.), 16590075 (to H. K.), and 14082207 (to K. S.) from the Ministry of Education, Science, Culture, and Sports of Japan (MEXT), the Human Frontier Science Program (to K. S.), and the Swedish Research Council 0652 (to T. B. and E. T.). 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 Research fellow of the Japan Society for the Promotion of Science.

² To whom correspondence may be addressed: Laboratory of Proteoglycan Signaling and Therapeutics, Graduate School of Life Science, Hokkaido University, Frontier Research Center for Post-Genomic Science and Technology, Nishi 11-choume, Kita 21-jo, Kita-ku, Sapporo, Hokkaido 001-0021, Japan. Tel.: 81-11-706-9054; Fax: 81-11-706-9056; E-mail: k-sugar{at}sci.hokudai.ac.jp. ³ To whom correspondence may be addressed: Dept. of Biochemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan. Tel.: 81-78-441-7570; Fax: 81-78-441-7571; E-mail: kitagawa{at}kobepharma-u.ac.jp.

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