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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / chemistry
-
Adaptor Proteins, Signal Transducing / genetics
-
Adaptor Proteins, Signal Transducing / metabolism*
-
Amino Acid Sequence
-
Animals
-
B-Cell CLL-Lymphoma 10 Protein
-
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
-
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
-
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*
Substances
-
Adaptor Proteins, Signal Transducing
-
B-Cell CLL-Lymphoma 10 Protein
-
BCL10 protein, human
-
Lipopolysaccharides
-
NF-kappa B
-
Neoplasm Proteins
-
Nuclear Proteins
-
Peli2 protein, mouse
-
TNF Receptor-Associated Factor 6
-
Toll-Like Receptor 4
-
Interleukin-1 Receptor-Associated Kinases
-
MAP Kinase Kinase Kinases
-
MAP kinase kinase kinase 7
-
Caspases
-
Malt1 protein, mouse
-
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein