Access

Letters to Nature

Nature 420, 324-329 (21 November 2002) | doi:10.1038/nature01182; Received 1 July 2002; Accepted 9 September 2002

Open Innovation Challenges

naturejobs

More science jobs
Post a job for free

Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4

Masahiro Yamamoto1,2, Shintaro Sato1,2, Hiroaki Hemmi1,2, Hideki Sanjo1,2, Satoshi Uematsu1,2, Tsuneyasu Kaisho1,2,3, Katsuaki Hoshino1,2, Osamu Takeuchi1,2, Masaya Kobayashi1,2, Takashi Fujita4, Kiyoshi Takeda1,2 & Shizuo Akira1,2

  1. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
  2. Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
  3. RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
  4. Department of Tumor Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan

Correspondence to: Shizuo Akira1,2 Correspondence and requests for materials should be addressed to S.A. (e-mail: Email: sakira@biken.osaka-u.ac.jp).

Top

Signal transduction through Toll-like receptors (TLRs) originates from their intracellular Toll/interleukin-1 receptor (TIR) domain, which binds to MyD88, a common adaptor protein containing a TIR domain1, 2, 3, 4. Although cytokine production is completely abolished in MyD88-deficient mice, some responses to lipopolysaccharide (LPS), including the induction of interferon-inducible genes and the maturation of dendritic cells, are still observed5, 6, 7. Another adaptor, TIRAP (also known as Mal), has been cloned as a molecule that specifically associates with TLR4 and thus may be responsible for the MyD88-independent response8, 9. Here we report that LPS-induced splenocyte proliferation and cytokine production are abolished in mice lacking TIRAP. As in MyD88-deficient mice, LPS activation of the nuclear factor NF-kappaB and mitogen-activated protein kinases is induced with delayed kinetics in TIRAP-deficient mice5. Expression of interferon-inducible genes and the maturation of dendritic cells is observed in these mice; they also show defective response to TLR2 ligands, but not to stimuli that activate TLR3, TLR7 or TLR9. In contrast to previous suggestions, our results show that TIRAP is not specific to TLR4 signalling and does not participate in the MyD88-independent pathway. Instead, TIRAP has a crucial role in the MyD88-dependent signalling pathway shared by TLR2 and TLR4.