Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking

Ryutaro Fukui; Shin-Ichiroh Saitoh; Atsuo Kanno; Masahiro Onji; Takuma Shibata; Akihiko Ito; Morikazu Onji; Mitsuru Matsumoto; Shizuo Akira; Nobuaki Yoshida; Kensuke Miyake

doi:10.1016/j.immuni.2011.05.010

Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking

Immunity. 2011 Jul 22;35(1):69-81. doi: 10.1016/j.immuni.2011.05.010. Epub 2011 Jun 16.

Authors

Ryutaro Fukui¹, Shin-Ichiroh Saitoh, Atsuo Kanno, Masahiro Onji, Takuma Shibata, Akihiko Ito, Morikazu Onji, Mitsuru Matsumoto, Shizuo Akira, Nobuaki Yoshida, Kensuke Miyake

Affiliation

¹ 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.

PMID: 21683627
DOI: 10.1016/j.immuni.2011.05.010

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
B-Lymphocytes / pathology
Cell Differentiation
Cells, Cultured
Inflammation
Lymphocyte Depletion
Membrane Glycoproteins / genetics
Membrane Glycoproteins / immunology
Membrane Glycoproteins / metabolism*
Membrane Transport Proteins / genetics
Membrane Transport Proteins / immunology
Membrane Transport Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Mutation / genetics
Protein Binding / genetics
Protein Transport
Th1 Cells / immunology
Th1 Cells / metabolism*
Th1 Cells / pathology
Th17 Cells / immunology
Th17 Cells / metabolism*
Th17 Cells / pathology
Toll-Like Receptor 7 / genetics
Toll-Like Receptor 7 / immunology
Toll-Like Receptor 7 / metabolism*
Toll-Like Receptor 9 / genetics
Toll-Like Receptor 9 / immunology
Toll-Like Receptor 9 / metabolism*

Substances

Membrane Glycoproteins
Membrane Transport Proteins
Tlr7 protein, mouse
Tlr9 protein, mouse
Toll-Like Receptor 7
Toll-Like Receptor 9
UNC93B1 protein, mouse