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

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

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