title: Identification of Lps2 as a key transducer of MyD88-independent TIR signalling.
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.
authors.affiliation: Department of Immunology, IMM-31, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: K
authors.initials: K
authors.lastname: Hoebe
authors.forename: X
authors.initials: X
authors.lastname: Du
authors.forename: P
authors.initials: P
authors.lastname: Georgel
authors.forename: E
authors.initials: E
authors.lastname: Janssen
authors.forename: K
authors.initials: K
authors.lastname: Tabeta
authors.forename: S O
authors.initials: SO
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Goode
authors.forename: P
authors.initials: P
authors.lastname: Lin
authors.forename: N
authors.initials: N
authors.lastname: Mann
authors.forename: S
authors.initials: S
authors.lastname: Mudd
authors.forename: K
authors.initials: K
authors.lastname: Crozat
authors.forename: S
authors.initials: S
authors.lastname: Sovath
authors.forename: J
authors.initials: J
authors.lastname: Han
authors.forename: B
authors.initials: B
authors.lastname: Beutler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D004926:Escherichia coli / Q000502:physiology; D006720:Homozygote; D007370:Interferon Type I / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000821:virology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D053594:Myeloid Differentiation Factor 88; D010641:Phenotype; D020161:Physical Chromosome Mapping; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000187:drug effects*; D013379:Substrate Specificity; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014616:Vaccinia virus / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D007370:Interferon Type I; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse