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

Research output: Contribution to journalArticle

68 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
Publication statusPublished - 2006 Jan 1
Externally publishedYes

Fingerprint

Signal Transducing Adaptor Proteins
Macrophages
Proteins
Phosphotransferases
Interleukin-6

ASJC Scopus subject areas

  • Immunology

Cite this

Sekine, Y., Yumioka, T., Yamamoto, T., Muromoto, R., Imoto, S., Sugiyma, K., ... 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.

Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages. / Sekine, Yuichi; Yumioka, Taro; Yamamoto, Tetsuya; Muromoto, Ryuta; Imoto, Seiyu; Sugiyma, Kenji; Oritani, Kenji; Shimoda, Kazuya; Minoguchi, Mayu; Akira, Shizuo; Yoshimura, Akihiko; Matsuda, Tadashi.

In: Journal of Immunology, Vol. 176, No. 1, 01.01.2006, p. 380-389.

Research output: Contribution to journalArticle

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, vol. 176, no. 1, pp. 380-389.
Sekine Y, Yumioka T, Yamamoto T, Muromoto R, Imoto S, Sugiyma K et al. Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages. Journal of Immunology. 2006 Jan 1;176(1):380-389.
Sekine, Yuichi ; Yumioka, Taro ; Yamamoto, Tetsuya ; Muromoto, Ryuta ; Imoto, Seiyu ; Sugiyma, Kenji ; Oritani, Kenji ; Shimoda, Kazuya ; Minoguchi, Mayu ; Akira, Shizuo ; Yoshimura, Akihiko ; Matsuda, Tadashi. / Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages. In: Journal of Immunology. 2006 ; Vol. 176, No. 1. pp. 380-389.
@article{23290719fe0a432fa10547f83e9e7c92,
title = "Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages",
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.",
author = "Yuichi Sekine and Taro Yumioka and Tetsuya Yamamoto and Ryuta Muromoto and Seiyu Imoto and Kenji Sugiyma and Kenji Oritani and Kazuya Shimoda and Mayu Minoguchi and Shizuo Akira and Akihiko Yoshimura and Tadashi Matsuda",
year = "2006",
month = "1",
day = "1",
language = "English",
volume = "176",
pages = "380--389",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "1",

}

TY - JOUR

T1 - Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages

AU - Sekine, Yuichi

AU - Yumioka, Taro

AU - Yamamoto, Tetsuya

AU - Muromoto, Ryuta

AU - Imoto, Seiyu

AU - Sugiyma, Kenji

AU - Oritani, Kenji

AU - Shimoda, Kazuya

AU - Minoguchi, Mayu

AU - Akira, Shizuo

AU - Yoshimura, Akihiko

AU - Matsuda, Tadashi

PY - 2006/1/1

Y1 - 2006/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=29644441336&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=29644441336&partnerID=8YFLogxK

M3 - Article

C2 - 16365431

AN - SCOPUS:29644441336

VL - 176

SP - 380

EP - 389

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

ER -