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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport / chemistry
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Adaptor Proteins, Vesicular Transport / metabolism*
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Amino Acid Sequence
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Blotting, Northern
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Carrier Proteins / chemistry
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Carrier Proteins / metabolism*
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Cell Line
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Cloning, Molecular
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Cytoplasm / metabolism
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DNA, Complementary / metabolism
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DNA-Binding Proteins / metabolism
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Dendritic Cells / metabolism
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Enzyme Activation
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Fungal Proteins / metabolism
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Genes, Dominant
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Genes, Reporter
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HeLa Cells
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Humans
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Interferon Regulatory Factor-3
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Interferon-beta / metabolism*
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Lipopolysaccharides / metabolism
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Membrane Glycoproteins / metabolism
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Molecular Sequence Data
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NF-kappa B / metabolism
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Precipitin Tests
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Promoter Regions, Genetic
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Protein Binding
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Protein Structure, Tertiary
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RNA Interference
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Receptors, Cell Surface / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Homology, Amino Acid
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Tissue Distribution
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Toll-Like Receptor 2
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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Transcription Factors / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Carrier Proteins
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DNA, Complementary
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DNA-Binding Proteins
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Fungal Proteins
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Lipopolysaccharides
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Membrane Glycoproteins
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NF-kappa B
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RNA, Messenger
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RNA, Small Interfering
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Receptors, Cell Surface
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TICAM1 protein, human
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TICAM2 protein, human
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TLR2 protein, human
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TLR3 protein, human
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TLR4 protein, human
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Toll-Like Receptor 2
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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Transcription Factors
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Interferon-beta
Associated data
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GENBANK/AB091054
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GENBANK/AB100441