Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages.
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-kappaB 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 IkappaB kinase (IKK)-alphabeta, but not TNFR-associated factor 6 or IL-1R-associated kinase 1, and formed a functional complex composed of MyD88-STAP-2-IKK-alphabeta. These interactions augmented MyD88- and/or IKK-alphabeta-dependent signals, leading to enhancement of the NF-kappaB activity. These results demonstrate that STAP-2 may constitute an alternative LPS/TLR4 pathway for NF-kappaB activation instead of the TNFR-associated factor 6-IL-1R-associated kinase 1 pathway.
Sekine
Yuichi
Y
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Yumioka
Taro
T
Yamamoto
Tetsuya
T
Muromoto
Ryuta
R
Imoto
Seiyu
S
Sugiyma
Kenji
K
Oritani
Kenji
K
Shimoda
Kazuya
K
Minoguchi
Mayu
M
Akira
Shizuo
S
Yoshimura
Akihiko
A
Matsuda
Tadashi
T
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D024202:Electrophoretic Mobility Shift Assay; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000276:immunology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase