Document Type
Article
Publication Date
8-5-2024
Identifier
DOI: 10.1084/jem.20232005; PMCID: PMC11116816
Abstract
Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.
Journal Title
The Journal of experimental medicine
Volume
221
Issue
8
MeSH Keywords
Animals; Humans; Mice; Autoimmunity; Membrane Transport Proteins; DNA Mutational Analysis; Toll-Like Receptors; Mutation; Female; Male; Mice, Inbred C57BL; HEK293 Cells; Toll-Like Receptor 7; Autoimmune Diseases
Keywords
Autoimmunity; Membrane Transport Proteins; DNA Mutational Analysis; Toll-Like Receptors; Mutation; Mice, Inbred C57BL; HEK293 Cells; Toll-Like Receptor 7; Autoimmune Diseases
Recommended Citation
Rael VE, Yano JA, Huizar JP, et al. Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans. J Exp Med. 2024;221(8):e20232005. doi:10.1084/jem.20232005
Comments
This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
Publisher's Link: https://rupress.org/jem/article/221/8/e20232005/276771/Large-scale-mutational-analysis-identifies-UNC93B1