Identification of Lps2 as a key transducer of MyD88-independent TIR signalling

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 and B. Beutler ()
Additional contact information
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

Nature, 2003, vol. 424, issue 6950, 743-748

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature01889

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