The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals.
The CATERPILLER (CLR, also NOD and NLR) proteins share structural similarities with the nucleotide binding domain (NBD)-leucine-rich repeat (LRR) superfamily of plant disease-resistance (R) proteins and are emerging as important immune regulators in animals. CLR proteins contain NBD-LRR motifs and are linked to a limited number of distinct N-terminal domains ... including transactivation, CARD (caspase activation and recruitment), and pyrin domains (PyD). The CLR gene, Monarch-1/Pypaf7, is expressed by resting primary myeloid/monocytic cells, and its expression in these cells is reduced by Toll-like receptor (TLR) agonists tumor necrosis factor (TNF) alpha and Mycobacterium tuberculosis. Monarch-1 reduces NFkappaB activation by TLR-signaling molecules MyD88, IRAK-1 (type I interleukin-1 receptor-associated protein kinase), and TRAF6 (TNF receptor (TNFR)-associated factor) as well as TNFR signaling molecules TRAF2 and RIP1 but not the downstream NFkappaB subunit p65. This indicates that Monarch-1 is a negative regulator of both TLR and TNFR pathways. Reducing Monarch-1 expression with small interference RNA in myeloid/monocytic cells caused a dramatic increase in NFkappaB activation and cytokine expression in response to TLR2/TLR4 agonists, TNFalpha, or M. tuberculosis infection, suggesting that Monarch-1 is a negative regulator of inflammation. Because Monarch-1 is the first CLR protein that interferes with both TLR2 and TLR4 activation, the mechanism of this interference is significant. We find that Monarch-1 associates with IRAK-1 but not MyD88, resulting in the blockage of IRAK-1 hyperphosphorylation. Mutants containing the NBD-LRR or PyD-NBD also blocked IRAK-1 activation. This is the first example of a CLR protein that antagonizes inflammatory responses initiated by TLR agonists via interference with IRAK-1 activation.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Antigens, Differentiation, Caspases, Cell Line, Cytokines, Cytoskeletal Proteins, Enzyme-Linked Immunosorbent Assay, Genes, Reporter, Humans, Immunoprecipitation, Inflammation, Interleukin-1 Receptor-Associated Kinases, Intracellular Signaling Peptides and Proteins, Luciferases, Monocytes, Mycobacterium tuberculosis, Myeloid Differentiation Factor 88, NF-kappa B, Nuclear Pore Complex Proteins, Phosphorylation, Plasmids, Promoter Regions, Genetic, Protein Kinases, Protein Structure, Tertiary, RNA, RNA, Small Interfering, RNA-Binding Proteins, Receptors, Immunologic, Retroviridae, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Factor 6, Toll-Like Receptors, Transcription Factor RelA, Transcriptional Activation, Transfection, Tumor Necrosis Factor-alpha
Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Antigens, Differentiation, Caspases, Cell Line, Cytokines, Cytoskeletal Proteins, Enzyme-Linked Immunosorbent Assay, Genes, Reporter, Humans, Immunoprecipitation, Inflammation, Interleukin-1 Receptor-Associated Kinases, Intracellular Signaling Peptides and Proteins, Luciferases, Monocytes, Mycobacterium tuberculosis, Myeloid Differentiation Factor 88, NF-kappa B, Nuclear Pore Complex Proteins, Phosphorylation, Plasmids, Promoter Regions, Genetic, Protein Kinases, Protein Structure, Tertiary, RNA, RNA, Small Interfering, RNA-Binding Proteins, Receptors, Immunologic, Retroviridae, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, TNF Receptor-Associated Factor 2, TNF Receptor-Associated Factor 6, Toll-Like Receptors, Transcription Factor RelA, Transcriptional Activation, Transfection, Tumor Necrosis Factor-alpha
J. Biol. Chem.
Date: Dec. 02, 2005
PubMed ID: 16203735
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