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J. Biol. Chem., Vol. 279, Issue 47, 48588-48597, November 19, 2004

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Sensing Bacterial Flagellin by Membrane and Soluble Orthologs of Toll-like Receptor 5 in Rainbow Trout (Onchorhynchus mikiss)^*

Tadayuki Tsujita¶, Hironobu Tsukada¶, Miki Nakao||, Hiroyuki Oshiumi, Misako Matsumoto, and Tsukasa Seya**

From the Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537-8511, Japan, the Department of Molecular Immunology Nara Institute of Science and Technology, Ikoma, Nara 631-0101, Japan, the ^||Laboratory of Marine Biochemistry, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka 812-8582, Japan, and the ^**Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8637 Japan

Rainbow trout (Onchorhynchus mikiss) possess two genes encoding putative leucine-rich repeat (LRR)-containing proteins similar to human TLR5. Molecular cloning of these two LRR proteins suggested the presence of a TLR5-like membrane form (rtTLR5M) and a soluble form (rtTLR5S). Here we elucidated the primary structures and the unique combinational functions of these fish versions of TLR5. The LRR regions of rtTLR5S and rtTLR5M exhibited 81% homology and relatively high (35.6 and 33.7%) homology to the extracellular domains of human TLR5 (huTLR5). Thus, two distinct genes encode the TLR5 orthologs in fish, one of which has a consensus intracellular domain (TIR). In order to test their functions, we constructed fusion proteins with the LRR region of rtTLR5S (S-chimera) or that of rtTLR5M and the TIR of huTLR5 (M-chimera). The S- and M-chimeras expressed in HeLa or CHO cells signaled the presence of Vibrio anguillarum flagellin, resulting in NF-B activation. rtTLR5M was ubiquitously expressed, whereas rtTLR5S was predominantly expressed in the liver. In the hepatoma cell lines of the rainbow trout RTH-149, stimulation of rtTLR5M with V. anguillarum or its flagellin allowed the up-regulation of rtTLR5S. Flagellin-mediated NF-B activation was more significant in the presence of or simultaneous expression of rtTLR5S. Therefore, a two-step flagellin response occurred for host defense against bacterial infection in fish: (a) flagellin first induced basal activation of NF-B via membrane TLR5, facilitating the production of soluble TLR5 and minimal acute phase proteins, and (b) the inducible soluble TLR5 amplifies membrane TLR5-mediated cellular responses in a positive feedback fashion.

Received for publication, July 7, 2004 , and in revised form, August 10, 2004.

^* This work was supported in part by CREST, Japan Science and Technology Agency, grants-in-aid from the Ministry of Education, Science, and Culture (Scientific Research on Priority Areas), Zoonosis Control Project, and the Ministry of Health and Welfare, and by Center of Excellence of Nara Institute of Science and Technology. 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB062504 and AB091105.

^¶ The first two authors contributed equally to this investigation.

To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8637 Japan. Tel.: 81-11-706-5073; Fax: 81-11-706-7866; E-mail: seya-tu{at}med.hokudai.ac.jp.

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