title: Transmembrane mutations in Toll-like receptor 9 bypass the requirement for ectodomain proteolysis and induce fatal inflammation.
abstract: Recognition of nucleic acids as a signature of infection by Toll-like receptors (TLRs) 7 and 9 exposes the host to potential self-recognition and autoimmunity. It has been proposed that intracellular compartmentalization is largely responsible for reliable self versus nonself discrimination by these receptors. We have previously shown that TLR9 and TLR7 require processing prior to activation, which may further reinforce receptor compartmentalization and tolerance to self, yet this possibility remains untested. Here we report that residues within the TLR9 transmembrane (TM) region conferred the requirement for ectodomain proteolysis. TLR9 TM mutants responded to extracellular DNA, and mice expressing such receptors died from systemic inflammation and anemia. This inflammatory disease did not require lymphocytes and appeared to require recognition of self-DNA by dendritic cells. To our knowledge, these results provide the first demonstration that TLR-intrinsic mutations can lead to a break in tolerance.
authors.affiliation: Division of Immunology & Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, 405 Life Sciences Addition, Berkeley, CA 94720-3200, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Mouchess
authors.forename: Nicholas
authors.initials: N
authors.lastname: Arpaia
authors.forename: Gianne
authors.initials: G
authors.lastname: Souza
authors.forename: Roman
authors.initials: R
authors.lastname: Barbalat
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Ewald
authors.forename: Laura
authors.initials: L
authors.lastname: Lau
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Barton
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D015870:Gene Expression; D005804:Genes, Lethal; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport; D059748:Proteolysis; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008024:Ligands; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta
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