Human TLR4 polymorphism D299G/T399I alters TLR4/MD-2 conformation and response to a weak ligand monophosphoryl lipid A

Natsuko Yamakawa, Umeharu Ohto, Sachiko Akashi-Takamura, Koichiro Takahashi, Shin Ichiroh Saitoh, Natsuko Tanimura, Takayoshi Suganami, Yoshihiro Ogawa, Takuma Shibata, Toshiyuki Shimizu, Kensuke Miyake

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A cell surface heterodimer Toll-like receptor 4 (TLR4)/MD-2 senses lipopolysaccharide (LPS), a principal membrane component of Gram-negative bacteria. LPS binds to MD-2 and induces dimerization of TLR4/MD-2. Dimerized TLR4 activates downstream signaling. TLR4 polymorphism replacing Asp299 with Gly and Thr399 with Ile (D299G/T399I) causes LPS hyporesponsiveness, and is associated with a variety of infectious and noninfectious diseases. However, a molecular mechanism underlying the LPS hyporesponsiveness remains controversial. We here asked whether the TLR4 polymorphism influenced cell surface expression of TLR4/MD-2, ligand-dependent TLR4/MD-2 dimerization or TLR4/ MD-2 responses to a weak agonist monophosphoryl lipid A (MPL). A newly established anti-TLR4 mAb detected D299G/T399I TLR4/MD-2 on Ba/F3 cells whereas a previous anti-TLR4 mAb did not, suggesting that the D299G/T399I polymorphism caused a conformational change in TLR4. Hyporesponsiveness of D299G/T399I TLR4/MD-2 was much more apparent when cells were stimulated with MPL than with lipid A. MPL-dependent TLR4/MD-2 dimerization was impaired by the D299G/T399I polymorphism. The D299G/T399I polymorphism did not alter LPS-binding to soluble TLR4/MD-2, but impaired its dimerization. These results suggest that the D299G/T399I TLR4 polymorphism impairs TLR4/MD-2 responses by altering ligand-dependent dimerization.

元の言語英語
ページ(範囲)45-52
ページ数8
ジャーナルInternational immunology
25
発行部数1
DOI
出版物ステータス出版済み - 1 2013

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Yamakawa, N., Ohto, U., Akashi-Takamura, S., Takahashi, K., Saitoh, S. I., Tanimura, N., Suganami, T., Ogawa, Y., Shibata, T., Shimizu, T., & Miyake, K. (2013). Human TLR4 polymorphism D299G/T399I alters TLR4/MD-2 conformation and response to a weak ligand monophosphoryl lipid A. International immunology, 25(1), 45-52. https://doi.org/10.1093/intimm/dxs084