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: Ryutaro Fukui, Shin-Ichiroh Saitoh, Atsuo Kanno, Masahiro Onji, Takuma Shibata, Akihiko Ito, Morikazu Onji, Mitsuru Matsumoto, Shizuo Akira, Nobuaki Yoshida, Kensuke Miyake
• Journal: Immunity (Immunity) Vol. 35 Issue 1 Pg. 69-81 (Jul 22 2011) ISSN: 1097-4180 [Electronic] United States
• PMID: 21683627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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