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| Identification of Lps2 as a key transducer of MyD88-independent TIR signalling |
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| Author(s): Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Kim SO, Goode J, Lin P, Mann N, Mudd S, Crozat K, Sovath S, Han J, Beutler B |
| Source: NATURE Volume: 424 Issue: 6950 Pages: 743-748 Published: AUG 14 2003 |
| Times Cited: 536 References: 32 |
| Abstract: In humans, ten Toll-like receptor (TLR) paralogues sense molecular components of microbes, initiating the production of cytokine mediators that create the inflammatory response. Using N-ethyl-N-nitrosourea, we induced a germline mutation called Lps2, which abolishes cytokine responses to double-stranded RNA and severely impairs responses to the endotoxin lipopolysaccharide (LPS), indicating that TLR3 and TLR4 might share a specific, proximal transducer. Here we identify the Lps2 mutation: a distal frameshift error in a Toll/interleukin-1 receptor/resistance (TIR) adaptor protein known as Trif or Ticam-1. Trif Lps2 homozygotes are markedly resistant to the toxic effects of LPS, and are hypersusceptible to mouse cytomegalovirus, failing to produce type I interferons when infected. Compound homozygosity for mutations at Trif and MyD88 (a cytoplasmic TIR-domain-containing adaptor protein) loci ablates all responses to LPS, indicating that only two signalling pathways emanate from the LPS receptor. However, a Trif-independent cell population is detectable when Trif Lps2 mutant macrophages are stimulated with LPS. This reveals that an alternative MyD88-dependent 'adaptor X' pathway is present in some, but not all, macrophages, and implies afferent immune specialization. |
| Document Type: Article |
| Language: English |
| Reprint Address: Beutler, B (reprint author), Scripps Res Inst, Dept Immunol, IMM-31,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA |
Addresses:
1. Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
2. La Jolla Inst Allergy & Immunol, Div Cellular Immunol, San Diego, CA 92121 USA |
| Publisher: NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 711HQ |
| ISSN: 0028-0836 |
| DOI: 10.1038/nature01889 |
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