HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 26, 18283-18291, June 27, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/26/18283    most recent M801013200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Funami, K. Articles by Matsumoto, M. PubMed PubMed Citation Articles by Funami, K. Articles by Matsumoto, M. Social Bookmarking                      What's this?

Homo-oligomerization Is Essential for Toll/Interleukin-1 Receptor Domain-containing Adaptor Molecule-1-mediated NF-B and Interferon Regulatory Factor-3 Activation^*

From the Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan

Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (TICAM-1, also named TIR domain-containing adaptor-inducing interferon (IFN)-β or TRIF)) is a signaling adaptor of Toll-like receptor (TLR) 3/4 that activates the transcription factors, interferon regulatory factor-3 (IRF-3) and NF-B leading to inducing IFN-β production. The mechanisms by which TICAM-1 is activated by TLR3/4 to serve as a signaling platform are unknown. In this study, we show that homo-oligomerization of TICAM-1 is critical for TICAM-1-mediated activation of NF-B and IRF-3. Both TIR and C-terminal domain of TICAM-1 mediated TICAM-1 oligomerization. Pro⁴³⁴ located in the TIR domain and the C-terminal region, with the exception of the RIP homotypic-interacting motif, were determinants of TICAM-1 oligomerization. Mutation of TIR domain (P434H) or deletion of C-terminal domain greatly reduced TICAM-1-mediated NF-B and IFN-β promoter activation. TICAM-1 oligomerization at either the TIR domain or the C-terminal region resulted in recruitment of tumor necrosis factor receptor-associated factor 3, a downstream signaling molecule essential for TICAM-1-mediated IRF-3 activation, but not recruitment of the IRF-3 kinase complex, NF-B-activating kinase-associated protein 1 and TANK-binding kinase 1. In addition, RIP homotypic-interacting motif mutant, which possesses two oligomerization motifs but not the RIP1 binding motif, also failed to recruit NF-B-activating kinase-associated protein 1 and TANK-binding kinase 1. Thus, full activation and formation of TICAM-1 signalosomes requires oligomerization induced at two different sites and RIP1 binding.

Received for publication, February 7, 2008 , and in revised form, April 22, 2008.

^* This work was supported by Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, and by Grants-in-Aid from the Ministry of Education, Science, and Culture (Specified Project for Advanced Research) and the hepatitis C virus project of the National Institutes of Health of Japan, and by the Uehara Memorial Foundation, Mitsubishi Foundation, Takeda Foundation, and NorthTec Foundation. 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 Both authors contributed equally to this work.

² Center for Integrated Medical Research, Keio University, Tokyo 160-8582, Japan.

³ Dept. of Immunobiology, Yale University School of Medicine, New Haven, CT 06510.

⁴ To whom correspondence should be addressed. Tel.: 81-11-706-6056; Fax: 81-11-706-7866; E-mail: matumoto{at}pop.med.hokudai.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Matsuo, H. Oshiumi, T. Tsujita, H. Mitani, H. Kasai, M. Yoshimizu, M. Matsumoto, and T. Seya Teleost TLR22 Recognizes RNA Duplex to Induce IFN and Protect Cells from Birnaviruses J. Immunol., September 1, 2008; 181(5): 3474 - 3485. [Abstract] [Full Text] [PDF]

				M. Shingai, M. Azuma, T. Ebihara, M. Sasai, K. Funami, M. Ayata, H. Ogura, H. Tsutsumi, M. Matsumoto, and T. Seya Soluble G protein of respiratory syncytial virus inhibits Toll-like receptor 3/4-mediated IFN-beta induction Int. Immunol., September 1, 2008; 20(9): 1169 - 1180. [Abstract] [Full Text] [PDF]