PMID:16831874

Citation	Dong, W, Liu, Y, Peng, J, Chen, L, Zou, T, Xiao, H, Liu, Z, Li, W, Bu, Y and Qi, Y (2006) The IRAK-1-BCL10-MALT1-TRAF6-TAK1 cascade mediates signaling to NF-kappaB from Toll-like receptor 4. J. Biol. Chem. 281:26029-40
Abstract	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.
Links	PubMed Online version:10.1074/jbc.M513057200
Keywords	Adaptor Proteins, Signal Transducing/chemistry; Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Amino Acid Sequence; Animals; Caspases/genetics; Caspases/metabolism; Cell Line; Dimerization; Humans; Interleukin-1 Receptor-Associated Kinases/chemistry; Interleukin-1 Receptor-Associated Kinases/genetics; Interleukin-1 Receptor-Associated Kinases/metabolism; Lipopolysaccharides/immunology; MAP Kinase Kinase Kinases/genetics; MAP Kinase Kinase Kinases/metabolism; Macrophages/cytology; Macrophages/metabolism; Mice; Molecular Sequence Data; NF-kappa B/metabolism; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Nuclear Proteins/metabolism; Protein Structure, Quaternary; RNA Interference; Signal Transduction/physiology; TNF Receptor-Associated Factor 6/genetics; TNF Receptor-Associated Factor 6/metabolism; Toll-Like Receptor 4/genetics; Toll-Like Receptor 4/metabolism
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