International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 207 - POSITIONAL CLONING OF LPS2, A KEY TRANSDUCER OF MYD88-INDEPENDENT TIR SIGNALING

Hoebe K
Scripps Research Institute

Co-Authors: 1) Du X, 1) Georgel P, 2) Janssen E, 1) Tabeta K, 1) Kim SO, 1) Goode J, 1) Mann N, 1) Mudd S, 1) Crozat K, 1) Sovath S, 1) Han J, 1) Beutler B
Institutions: 1) Scripps Research Institute, 2) La Jolla Institute of Allergy and Immunology

Using ENU mutagenesis, we have examined more than 9,000 mice for defects in responses to Toll-like receptor (TLR) agonists. The Lps2 phenotype was identified as a MyD88-independent TLR signaling defect, characterized by absence of responses to dsRNA and severe impairment of responses to LPS. The existence of Lps2 suggested that TLR3 and TLR4 might share a proximal transducer. The mutation was mapped on a total of 1567 meioses, and confined to a critical region that encompassed 216 kb of DNA. The entire critical region was sequenced by amplifying it in 63 overlapping 4 kb segments. The Lps2 mutation was identified as the sole mutational defect within the critical region, and was found to be a distal frameshift error in a TIR adapter protein known as TRIF or TICAM-1. TrifLps2 homozygotes are markedly resistant to the toxic effects of LPS, and hypersusceptible to mouse cytomegalovirus, failing to produce type I interferons when infected. In addition, Trif is absolutely required for the adjuvant effect of LPS, and homozygotes for the mutation fail to upregulate costimulatory molecules such as CD40, CD80 and CD86, leading to an impaired adaptive immune response. Compound homozygosity for mutations at Trif and MyD88 loci ablates all responses to LPS, indicating that two and only two signaling pathways emanate from the LPS receptor. However, a “Trif-independent” cell population is detectable when TrifLps2 mutant macrophages are stimulated with LPS.


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