title: Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking.
abstract: Toll-like receptor-7 (TLR7) and 9, innate immune sensors for microbial RNA or DNA, have been implicated in autoimmunity. Upon activation, TLR7 and 9 are transported from the endoplasmic reticulum (ER) to endolysosomes for nucleic acid sensing by an ER-resident protein, Unc93B1. Little is known, however, about a role for sensor transportation in controlling autoimmunity. TLR9 competes with TLR7 for Unc93B1-dependent trafficking and predominates over TLR7. TLR9 skewing is actively maintained by Unc93B1 and reversed to TLR7 if Unc93B1 loses preferential binding via a D34A mutation. We here demonstrate that mice harboring a D34A mutation showed TLR7-dependent, systemic lethal inflammation. CD4(+) T cells showed marked differentiation toward T helper 1 (Th1) or Th17 cell subsets. B cell depletion abolished T cell differentiation and systemic inflammation. Thus, Unc93B1 controls homeostatic TLR7 activation by balancing TLR9 to TLR7 trafficking.
authors.affiliation: Division of Infectious Genetics, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108-8639, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Fukui
authors.forename: Shin-Ichiroh
authors.initials: S
authors.lastname: Saitoh
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kanno
authors.forename: Masahiro
authors.initials: M
authors.lastname: Onji
authors.forename: Takuma
authors.initials: T
authors.lastname: Shibata
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
authors.forename: Morikazu
authors.initials: M
authors.lastname: Onji
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yoshida
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D007249:Inflammation; D008212:Lymphocyte Depletion; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C512254:UNC93B1 protein, mouse