Victoria E Rael, Julian A Yano, John P Huizar, Leianna C Slayden, Madeleine A Weiss, Elizabeth A Turcotte, Jacob M Terry, Wenqi Zuo, Isabelle Thiffault, Tomi Pastinen, Emily G Farrow, Janda L Jenkins, Mara L Becker, Stephen C Wong, Anne M Stevens, Catherine Otten, Eric J Allenspach, Devon E Bonner, Jonathan A Bernstein, Matthew T Wheeler, Robert A Saxton, Bo Liu, Olivia Majer, Gregory M Barton
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...
August 5, 2024: Journal of Experimental Medicine