| http://purl.uniprot.org/citations/24194546 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/24194546 | http://www.w3.org/2000/01/rdf-schema#comment | "Toll/IL-1R resistance (TIR) domain-containing adapter-inducing IFN-β (TRIF) is a Toll-like receptor (TLR) adapter that mediates MyD88-independent induction of type I interferons through activation of IFN regulatory factor 3 and NFκB. We have examined peptides derived from the TRIF TIR domain for ability to inhibit TLR4. In addition to a previously identified BB loop peptide (TF4), a peptide derived from putative helix B of TRIF TIR (TF5) strongly inhibits LPS-induced cytokine and MAPK activation in wild-type cells. TF5 failed to inhibit LPS-induced cytokine and kinase activation in TRIF-deficient immortalized bone-marrow-derived macrophage, but was fully inhibitory in MyD88 knockout cells. TF5 does not block macrophage activation induced by TLR2, TLR3, TLR9, or retinoic acid-inducible gene 1/melanoma differentiation-associated protein 5 agonists. Immunoprecipitation assays demonstrated that TF4 binds to TLR4 but not TRIF-related adaptor molecule (TRAM), whereas TF5 binds to TRAM strongly and TLR4 to a lesser extent. Although TF5 prevented coimmunoprecipitation of TRIF with both TRAM and TLR4, site-directed mutagenesis of the TRIF B helix residues affected TRIF-TRAM coimmunoprecipitation selectively, as these mutations did not block TRIF-TLR4 association. These results suggest that the folded TRIF TIR domain associates with TRAM through the TRIF B helix region, but uses a different region for TRIF-TLR4 association. The B helix peptide TF5, however, can associate with either TRAM or TLR4. In a mouse model of TLR4-driven inflammation, TF5 decreased plasma cytokine levels and protected mice from a lethal LPS challenge. Our data identify TRIF sites that are important for interaction with TLR4 and TRAM, and demonstrate that TF5 is a potent TLR4 inhibitor with significant potential as a candidate therapeutic for human sepsis."xsd:string |
| http://purl.uniprot.org/citations/24194546 | http://purl.org/dc/terms/identifier | "doi:10.1073/pnas.1313575110"xsd:string |
| http://purl.uniprot.org/citations/24194546 | http://purl.uniprot.org/core/author | "Vogel S.N."xsd:string |
| http://purl.uniprot.org/citations/24194546 | http://purl.uniprot.org/core/author | "Sundberg E.J."xsd:string |
| http://purl.uniprot.org/citations/24194546 | http://purl.uniprot.org/core/author | "Piao W."xsd:string |
| http://purl.uniprot.org/citations/24194546 | http://purl.uniprot.org/core/author | "Toshchakov V.Y."xsd:string |
| http://purl.uniprot.org/citations/24194546 | http://purl.uniprot.org/core/author | "Piepenbrink K.H."xsd:string |
| http://purl.uniprot.org/citations/24194546 | http://purl.uniprot.org/core/author | "Ru L.W."xsd:string |
| http://purl.uniprot.org/citations/24194546 | http://purl.uniprot.org/core/date | "2013"xsd:gYear |
| http://purl.uniprot.org/citations/24194546 | http://purl.uniprot.org/core/name | "Proc Natl Acad Sci U S A"xsd:string |
| http://purl.uniprot.org/citations/24194546 | http://purl.uniprot.org/core/pages | "19036-19041"xsd:string |
| http://purl.uniprot.org/citations/24194546 | http://purl.uniprot.org/core/title | "Recruitment of TLR adapter TRIF to TLR4 signaling complex is mediated by the second helical region of TRIF TIR domain."xsd:string |
| http://purl.uniprot.org/citations/24194546 | http://purl.uniprot.org/core/volume | "110"xsd:string |
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