The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport

Karin Pelka; Damien Bertheloot; Elisa Reimer; Kshiti Phulphagar; Susanne V Schmidt; Anette Christ; Rainer Stahl; Nicki Watson; Kensuke Miyake; Nir Hacohen; Albert Haas; Melanie M Brinkmann; Ann Marshak-Rothstein; Felix Meissner; Eicke Latz

doi:10.1016/j.immuni.2018.04.011

The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport

Immunity. 2018 May 15;48(5):911-922.e7. doi: 10.1016/j.immuni.2018.04.011.

Authors

Affiliations

¹ Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany; IFM Therapeutics GmbH, 53127 Bonn, Germany.
³ Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
⁴ Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany; Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
⁵ Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany.
⁶ Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany; Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
⁷ W.M. Keck Microscopy Facility, the Whitehead Institute, Cambridge, MA 02142, USA.
⁸ Division of Innate Immunity, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108 8639, Japan; Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo 108 8639, Japan.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁰ Cell Biology Institute, University of Bonn, 53121 Bonn, Germany.
¹¹ Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
¹² Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
¹³ Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany; Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; German Center for Neurodegenerative Diseases, 53175 Bonn, Germany. Electronic address: eicke.latz@uni-bonn.de.

Abstract

Unc-93 homolog B1 (UNC93B1) is a key regulator of nucleic acid (NA)-sensing Toll-like receptors (TLRs). Loss of NA-sensing TLR responses in UNC93B1-deficient patients facilitates Herpes simplex virus type 1 (HSV-1) encephalitis. UNC93B1 is thought to guide NA-sensing TLRs from the endoplasmic reticulum (ER) to their respective endosomal signaling compartments and to guide the flagellin receptor TLR5 to the cell surface, raising the question of how UNC93B1 mediates differential TLR trafficking. Here, we report that UNC93B1 regulates a step upstream of the differential TLR trafficking process. We discovered that UNC93B1 deficiency resulted in near-complete loss of TLR3 and TLR7 proteins in primary splenic mouse dendritic cells and macrophages, showing that UNC93B1 is critical for maintaining TLR expression. Notably, expression of an ER-retained UNC93B1 version was sufficient to stabilize TLRs and largely restore endosomal TLR trafficking and activity. These data are critical for an understanding of how UNC93B1 can regulate the function of a broad subset of TLRs.

Keywords: TLR; TLR trafficking; TLR13; TLR3; TLR7; TLR8; TLR9; Toll-like receptors; UNC93B; UNC93B1; nucleic acid sensing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dendritic Cells / immunology
Dendritic Cells / metabolism
Endoplasmic Reticulum / immunology
Endoplasmic Reticulum / metabolism
Endosomes / immunology*
Endosomes / metabolism
HEK293 Cells
Humans
Macrophages / immunology
Macrophages / metabolism
Membrane Transport Proteins / genetics
Membrane Transport Proteins / immunology*
Membrane Transport Proteins / metabolism
Mice, Inbred C57BL
Mice, Knockout
Molecular Chaperones / genetics
Molecular Chaperones / immunology*
Molecular Chaperones / metabolism
Protein Stability
Protein Transport / immunology
Signal Transduction / genetics
Signal Transduction / immunology
THP-1 Cells
Toll-Like Receptors / genetics
Toll-Like Receptors / immunology*
Toll-Like Receptors / metabolism

Substances

Membrane Transport Proteins
Molecular Chaperones
Toll-Like Receptors
UNC93B1 protein, mouse

Grants and funding

R01 AR066808/AR/NIAMS NIH HHS/United States