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J. Biol. Chem., Vol. 281, Issue 15, 10230-10235, April 14, 2006

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Targeted Disruption of Gb3/CD77 Synthase Gene Resulted in the Complete Deletion of Globo-series Glycosphingolipids and Loss of Sensitivity to Verotoxins^*

Tetsuya Okuda, Noriyo Tokuda, Shin-ichiro Numata, Masafumi Ito, Michio Ohta^¶, Kumiko Kawamura^¶, Joelle Wiels^||, Takeshi Urano, Orie Tajima, Keiko Furukawa, and Koichi Furukawa¹

From the Departments of Biochemistry II, Pathology, and ^¶Microbiology, Nagoya University School of Medicine, Tsurumai, Showa-ku, Nagoya 466-0065, Japan and ^||CNRS Unite Mixte de Recherche, Institut Gustave Roussy, Villejuif Cedex 94805, France

To examine whether globotriaosylceramide (Gb3/CD77) is a receptor for verotoxins (VTs) in vivo, sensitivity of Gb3/CD77 synthase null mutant mice to VT-2 and VT-1 was analyzed. Although wild-type mice died after administration of 0.02 µg of VT-2 or 1.0 µg of VT-1, the mutant mice showed no reaction to doses as much as 100 times that administered to wild types. Expression analysis of Gb3/CD77 in mouse tissues with antibody revealed that low, but definite, levels of Gb3/CD77 were expressed in the microvascular endothelial cells of the brain cortex and pia mater and in renal tubular capillaries. Corresponding to the Gb3/CD77 expression, tissue damage with edema, congestion, and cytopathic changes was observed, indicating that Gb3/CD77 (and its derivatives) exclusively function as a receptor for VTs in vivo. The lethal kinetics were similar regardless of lipopolysaccharide elimination in VT preparation, suggesting that basal Gb3/CD77 levels are sufficient for lethal effects of VTs.

Received for publication, January 4, 2006 , and in revised form, February 9, 2006.

^* This study was supported by Grant-in-aid 14082102 for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT). 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.: 81-52-744-2070; Fax: 81-52-744-2069; E-mail: koichi{at}med.nagoya-u.ac.jp.

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