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Modulation of TLR4 Signaling by a Novel Adaptor Protein Signal-Transducing Adaptor Protein-2 in Macrophages¹

Yuichi Sekine^*, Taro Yumioka^*, Tetsuya Yamamoto^*, Ryuta Muromoto^*, Seiyu Imoto^*, Kenji Sugiyma, Kenji Oritani, Kazuya Shimoda^¶, Mayu Minoguchi^||, Shizuo Akira, Akihiko Yoshimura^|| and Tadashi Matsuda^2,*

^* Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; Nippon Boehringer Ingelheim, Kawanishi Pharma Research Institute, Hyogo, Japan; Department of Hematology and Oncology, Graduate School of Medicine, and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and ^¶ First Department of Internal Medicine, Faculty of Medicine, and ^|| Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

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-B 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 IB kinase (IKK)-, but not TNFR-associated factor 6 or IL-1R-associated kinase 1, and formed a functional complex composed of MyD88-STAP-2-IKK-. These interactions augmented MyD88- and/or IKK--dependent signals, leading to enhancement of the NF-B activity. These results demonstrate that STAP-2 may constitute an alternative LPS/TLR4 pathway for NF-B activation instead of the TNFR-associated factor 6-IL-1R-associated kinase 1 pathway.

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