The IRAK-1-BCL10-MALT1-TRAF6-TAK1 cascade mediates signaling to NF-kappaB from Toll-like receptor 4.
Our previous studies have revealed that the signaling protein BCL10 plays a major role in adaptive immunity by mediating NF-kappaB activation in the LPS/TLR4 pathway. In this study, we show that IRAK-1 acts as the essential upstream adaptor that recruits BCL10 to the TLR4 signaling complex and mediates signaling to NF-kappaB through the BCL10-MALT1-TRAF6-TAK1 cascade. Following dissociation from IRAK-1, BCL10 is translocated into the cytosol along with TRAF6 and TAK1, in a process bridged by a direct BCL10-Pellino2 interaction. RNA interference against MALT1 markedly reduced the level of NF-kappaB activation stimulated by lipopolysaccharide (LPS) in macrophages, which suggests that MALT1 plays a major role in the LPS/TLR4 pathway. MALT1 interacted with BCL10 and TRAF6 to facilitate TRAF6 self-ubiquitination in the cytosol, which was strictly dependent on the dissociation of BCL10 from IRAK-1. We show that BCL10 oligomerization is a prerequisite for BCL10 function in LPS signaling to NF-kappaB and that IRAK-1 dimerization is an important event in this process.
Dong
Wei
W
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
Liu
Yingle
Y
Peng
Jinhong
J
Chen
Lu
L
Zou
Tingting
T
Xiao
Huazhong
H
Liu
Zhengxue
Z
Li
Wen
W
Bu
Yiwen
Y
Qi
Yipeng
Y
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D020836:Protein Structure, Quaternary; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D020169:Caspases; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D000099151:MAP Kinase Kinase Kinase 7; C118591:BCL10 protein, human; C485961:Peli2 protein, mouse; C498509:Malt1 protein, mouse