Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages

Yuichi Sekine, Taro Yumioka, Tetsuya Yamamoto, Ryuta Muromoto, Seiyu Imoto, Kenji Sugiyma, Kenji Oritani, Kazuya Shimoda, Mayu Minoguchi, Shizuo Akira, Akihiko Yoshimura, Tadashi Matsuda

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69 Citations (Scopus)

Abstract

Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin and Src homology 2-like domains as well as a YXXQ motif in its C-terminal region. Our previous studies have demonstrated that STAP-2 binds to STAT3 and STAT5, and regulates their signaling pathways. In the present study, STAP-2 was found to positively regulate LPS/TLR4-mediated signals in macrophages. Disruption of STAP-2 resulted in impaired LPS/TLR4-induced cytokine production and NF-κB activation. Conversely, overexpression of STAP-2 enhanced these LPS/TLR4-induced biological activities. STAP-2, particularly its Src homology 2-like domain, bound to both MyD88 and IκB kinase (IKK)-αβ, but not TNFR-associated factor 6 or IL-1R-associated kinase 1, and formed a functional complex composed of MyD88-STAP-2-IKK-αβ. These interactions augmented MyD88- and/or IKK-αβ-dependent signals, leading to enhancement of the NF-κB activity. These results demonstrate that STAP-2 may constitute an alternative LPS/TLR4 pathway for NF-κB activation instead of the TNFR-associated factor 6-IL-1R-associated kinase 1 pathway.

Original languageEnglish
Pages (from-to)380-389
Number of pages10
JournalJournal of Immunology
Volume176
Issue number1
DOIs
Publication statusPublished - 2006 Jan 1
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Sekine, Y., Yumioka, T., Yamamoto, T., Muromoto, R., Imoto, S., Sugiyma, K., Oritani, K., Shimoda, K., Minoguchi, M., Akira, S., Yoshimura, A., & Matsuda, T. (2006). Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages. Journal of Immunology, 176(1), 380-389. https://doi.org/10.4049/jimmunol.176.1.380