title: SIGIRR inhibits interleukin-1 receptor- and toll-like receptor 4-mediated signaling through different mechanisms.
abstract: The Toll-interleukin-1 receptor (TIR) domain-containing orphan receptor SIGIRR (single immunoglobulin interleukin-1 receptor-related protein) acts as a negative regulator of interleukin (IL)-1 and lipopolysaccharide (LPS) signaling. Endogenous SIGIRR transiently interacted with IL-1 receptor and the receptor-proximal signaling components (MyD88, IRAK, and tumor necrosis factor receptor-associated factor 6) upon IL-1 stimulation, indicating that SIGIRR interacts with the IL-1 receptor complex in a ligand-dependent manner. Similar interaction was also observed between SIGIRR and Toll-like receptor 4 receptor complex upon LPS stimulation. To identify the domains of SIGIRR required for its interaction with the Toll-like receptor 4 and IL-1 receptor complexes, several SIGIRR deletion mutants were generated, including DeltaN (lacking the extracellular immunoglobulin (Ig) domain with deletion of amino acids 1-119), DeltaC (lacking the C-terminal domain with deletion of amino acids 313-410), and DeltaTIR (lacking the TIR domain with deletion of amino acids 161-313). Whereas both the extracellular Ig domain and the intracellular TIR domains are important for SIGIRR to inhibit IL-1 signaling, only the TIR domain is necessary for SIGIRR to inhibit LPS signaling. The extracellular Ig domain exerts its inhibitory role in IL-1 signaling by interfering with the heterodimerization of IL-1 receptor and IL-1RAcP, whereas the intracellular TIR domain inhibits both IL-1 and LPS signaling by attenuating the recruitment of receptor-proximal signaling components to the receptor. These results indicate that SIGIRR inhibits IL-1 and LPS signaling pathways through differential mechanisms.
authors.affiliation: Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Jinzhong
authors.initials: J
authors.lastname: Qin
authors.forename: Youcun
authors.initials: Y
authors.lastname: Qian
authors.forename: Jianhong
authors.initials: J
authors.lastname: Yao
authors.forename: Cui
authors.initials: C
authors.lastname: Grace
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation / Q000378:metabolism; D001667:Binding, Competitive; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D017353:Gene Deletion; D006801:Humans; D047468:Immunoprecipitation; D007375:Interleukin-1 / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009154:Mutation; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004247:DNA; D007375:Interleukin-1; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides; D008156:Luciferases; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009841:Oligonucleotides; D011494:Protein Kinases; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C495345:TLR4 protein, human; C484529:SIGIRR protein, mouse