RRC ID 54462
Author Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya T.
Title TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta.
Journal J Biol Chem
Abstract Lipopolysaccharide (LPS) is an agonist for Toll-like receptor (TLR) 4 and expresses many genes including NF-kappaB- and interferon regulatory factor (IRF)-3/IFN-inducible genes in macrophages and dendritic cells (DCs). TICAM-1/TRIF was identified as an adapter that facilitates activation of IRF-3 followed by expression of interferon (IFN)-beta genes in TLR3 signaling, but TICAM-1 does not directly bind TLR4. Although MyD88 and Mal/TIRAP adapters functions downstream of TLR4, DC maturation and IFN-beta induction are independent of MyD88 and Mal/TIRAP. In this investigation, we report the identification of a novel adapter, TICAM-2, that physically bridges TLR4 and TICAM-1 and functionally transmits LPS-TLR4 signaling to TICAM-1, which in turn activates IRF-3. In its structural features, TICAM-2 resembled Mal/TIRAP, an adapter that links TLR2/4 and MyD88. However, TICAM-2 per se exhibited minimal ability to activate NF-kappaB and the IFN-beta promoter. Hence, in LPS signaling TLR4 recruits two types of adapters, TIRAP and TICAM-2, to its cytoplasmic domain that are indirectly connected to two effective adapters, MyD88 and TICAM-1, respectively. We conclude that for LPS-TLR4-mediated activation of IFN-beta, the adapter complex of TICAM-2 and TICAM-1 plays a crucial role. This results in the construction of MyD88-dependent and -independent pathways separately downstream of the two distinct adapters.
Volume 278(50)
Pages 49751-62
Published 2003-12-12
DOI 10.1074/jbc.M305820200
PII S0021-9258(20)75483-9
PMID 14519765
MeSH Adaptor Proteins, Signal Transducing* Adaptor Proteins, Vesicular Transport / chemistry Adaptor Proteins, Vesicular Transport / metabolism* Amino Acid Sequence Blotting, Northern Carrier Proteins / chemistry Carrier Proteins / metabolism* Cell Line Cloning, Molecular Cytoplasm / metabolism DNA, Complementary / metabolism DNA-Binding Proteins / metabolism Dendritic Cells / metabolism Enzyme Activation Fungal Proteins / metabolism Genes, Dominant Genes, Reporter HeLa Cells Humans Interferon Regulatory Factor-3 Interferon-beta / metabolism* Lipopolysaccharides / metabolism Membrane Glycoproteins / metabolism Molecular Sequence Data NF-kappa B / metabolism Precipitin Tests Promoter Regions, Genetic Protein Binding Protein Structure, Tertiary RNA Interference RNA, Messenger / metabolism RNA, Small Interfering / metabolism Receptors, Cell Surface / metabolism Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Amino Acid Tissue Distribution Toll-Like Receptor 2 Toll-Like Receptor 3 Toll-Like Receptor 4 Toll-Like Receptors Transcription Factors / metabolism
IF 4.238
Times Cited 287
DNA material human TICAM-2 expression vector (RDB16924) human TICAM-2 C Flag expression vector (RDB16926) human TICAM-2 C HA expression vector (RDB16928)
Human and Animal Cells 293(RCB1637)