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Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.

Publication ,  Journal Article
Rael, VE; Yano, JA; Huizar, JP; Slayden, LC; Weiss, MA; Turcotte, EA; Terry, JM; Zuo, W; Thiffault, I; Pastinen, T; Farrow, EG; Jenkins, JL ...
Published in: J Exp Med
August 5, 2024

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.

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Published In

J Exp Med

DOI

EISSN

1540-9538

Publication Date

August 5, 2024

Volume

221

Issue

8

Location

United States

Related Subject Headings

  • Toll-Like Receptors
  • Toll-Like Receptor 7
  • Mutation
  • Mice, Inbred C57BL
  • Mice
  • Membrane Transport Proteins
  • Male
  • Immunology
  • Humans
  • HEK293 Cells
 

Citation

APA
Chicago
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MLA
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Rael, V. E., Yano, J. A., Huizar, J. P., Slayden, L. C., Weiss, M. A., Turcotte, E. A., … Barton, G. M. (2024). Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans. J Exp Med, 221(8). https://doi.org/10.1084/jem.20232005
Rael, Victoria E., Julian A. Yano, John P. Huizar, Leianna C. Slayden, Madeleine A. Weiss, Elizabeth A. Turcotte, Jacob M. Terry, et al. “Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.J Exp Med 221, no. 8 (August 5, 2024). https://doi.org/10.1084/jem.20232005.
Rael VE, Yano JA, Huizar JP, Slayden LC, Weiss MA, Turcotte EA, et al. Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans. J Exp Med. 2024 Aug 5;221(8).
Rael, Victoria E., et al. “Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.J Exp Med, vol. 221, no. 8, Aug. 2024. Pubmed, doi:10.1084/jem.20232005.
Rael VE, Yano JA, Huizar JP, Slayden LC, Weiss MA, Turcotte EA, Terry JM, Zuo W, Thiffault I, Pastinen T, Farrow EG, Jenkins JL, Becker ML, Wong SC, Stevens AM, Otten C, Allenspach EJ, Bonner DE, Bernstein JA, Wheeler MT, Saxton RA, Undiagnosed Diseases Network, Liu B, Majer O, Barton GM. Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans. J Exp Med. 2024 Aug 5;221(8).

Published In

J Exp Med

DOI

EISSN

1540-9538

Publication Date

August 5, 2024

Volume

221

Issue

8

Location

United States

Related Subject Headings

  • Toll-Like Receptors
  • Toll-Like Receptor 7
  • Mutation
  • Mice, Inbred C57BL
  • Mice
  • Membrane Transport Proteins
  • Male
  • Immunology
  • Humans
  • HEK293 Cells