Author
Listed:
- K. Hoebe
(The Scripps Research Institute)
- X. Du
(The Scripps Research Institute)
- P. Georgel
(The Scripps Research Institute)
- E. Janssen
(La Jolla Institute for Allergy and Immunology)
- K. Tabeta
(The Scripps Research Institute)
- S. O. Kim
(The Scripps Research Institute)
- J. Goode
(The Scripps Research Institute)
- P. Lin
(The Scripps Research Institute)
- N. Mann
(The Scripps Research Institute)
- S. Mudd
(The Scripps Research Institute)
- K. Crozat
(The Scripps Research Institute)
- S. Sovath
(The Scripps Research Institute)
- J. Han
(The Scripps Research Institute)
- B. Beutler
(The Scripps Research Institute)
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. TrifLps2 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 TrifLps2 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.
Suggested Citation
K. Hoebe & X. Du & P. Georgel & E. Janssen & K. Tabeta & S. O. Kim & J. Goode & P. Lin & N. Mann & S. Mudd & K. Crozat & S. Sovath & J. Han & B. Beutler, 2003.
"Identification of Lps2 as a key transducer of MyD88-independent TIR signalling,"
Nature, Nature, vol. 424(6950), pages 743-748, August.
Handle:
RePEc:nat:nature:v:424:y:2003:i:6950:d:10.1038_nature01889
DOI: 10.1038/nature01889
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