Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans
Authors: Rael Victoria E. , Yano Julian A. , Huizar John P. , Slayden Leianna C. , Weiss Madeleine A. , Turcotte Elizabeth A. , Terry Jacob M. , Zuo Wenqi , Thiffault Isabelle , Pastinen Tomi , Farrow Emily G. , Jenkins Janda L. , Becker Mara L. , Wong Stephen C. , Stevens Anne M. , Otten Catherine , Allenspach Eric J. , Bonner Devon E. , Bernstein Jonathan A. , Wheeler Matthew T. , Saxton Robert A. ,   Undiagnosed Diseases Network, Acosta Maria T. , Adams David R. , Alvarez Raquel L. , Alvey Justin , Allworth Aimee , Andrews Ashley , Ashley Euan A. , Afzali Ben , Bacino Carlos A. , Bademci Guney , Balasubramanyam Ashok , Baldridge Dustin , Bale Jim , Bamshad Michael , Barbouth Deborah , Bayrak-Toydemir Pinar , Beck Anita , Beggs Alan H. , Behrens Edward , Bejerano Gill , Bellen Hugo J. , Bennett Jimmy , Bernstein Jonathan A. , Berry Gerard T. , Bican Anna , Bivona Stephanie , Blue Elizabeth , Bohnsack John , Bonner Devon , Botto Lorenzo , Briere Lauren C. , Brown Gabrielle , Burke Elizabeth A. , Burrage Lindsay C. , Butte Manish J. , Byers Peter , Byrd William E. , Carey John , Cassini Thomas , Chanprasert Sirisak , Chao Hsiao-Tuan , Chinn Ivan , Clark Gary D. , Coakley Terra R. , Cobban Laurel A. , Cogan Joy D. , Coggins Matthew , Cole F. Sessions , Colley Heather A. , Corona Rosario , Craigen William J. , Crouse Andrew B. , Cunningham Michael , D’Souza Precilla , Dai Hongzheng , Dasari Surendra , Davis Joie , Dayal Jyoti G. , Delgado Margaret , Dell’Angelica Esteban C. , Dipple Katrina , Doherty Daniel , Dorrani Naghmeh , Doss Argenia L. , Douine Emilie D. , Earl Dawn , Eckstein David J. , Emrick Lisa T. , Eng Christine M. , Falk Marni , Fieg Elizabeth L. , Fisher Paul G. , Fogel Brent L. , Fu Jiayu , Gahl William A. , Glass Ian , Goddard Page C. , Godfrey Rena A. , Gropman Andrea , Halley Meghan C. , Hamid Rizwan , Hanchard Neal , Hassey Kelly , Hayes Nichole , High Frances , Hing Anne , Hisama Fuki M. , Holm Ingrid A. , Hom Jason , Horike-Pyne Martha , Huang Alden , Huang Yan , Hutchison Sarah , Introne Wendy , Izumi Kosuke , Jarvik Gail P. , Jarvik Jeffrey , Jayadev Suman , Jean-Marie Orpa , Jobanputra Vaidehi , Kaitryn Emerald , Ketkar Shamika , Kiley Dana , Kilich Gonench , Kobren Shilpa N. , Kohane Isaac S. , Kohler Jennefer N. , Korrick Susan , Krakow Deborah , Krasnewich Donna M. , Kravets Elijah , Lalani Seema R. , Lam Christina , Lanpher Brendan C. , Lanza Ian R. , LeBlanc Kimberly , Lee Brendan H. , Lewis Richard A. , Liu Pengfei , Longo Nicola , Loo Sandra K. , Loscalzo Joseph , Maas Richard L. , Macnamara Ellen F. , MacRae Calum A. , Maduro Valerie V. , Maghiro AudreyStephannie , Mahoney Rachel , Malicdan May Christine V. , Mamounas Laura A. , Manolio Teri A. , Mao Rong , Marom Ronit , Marth Gabor , Martin Beth A. , Martin Martin G. , Martínez-Agosto Julian A. , Marwaha Shruti , McConkie-Rosell Allyn , McCray Alexa T. , McGee Elisabeth , Might Matthew , Mikati Mohamad , Miller Danny , Mirzaa Ghayda , Morava Eva , Moretti Paolo , Morimoto Marie , Mulvihill John J. , Nakano-Okuno Mariko , Nelson Stanley F. , Nieves-Rodriguez Shirley , Novacic Donna , Oglesbee Devin , Orengo James P. , Pace Laura , Pak Stephen , Pallais J. Carl , Papp Jeanette C. , Parker Neil H. , Petcharet Leoyklang , Phillips John A. , Posey Jennifer E. , Potocki Lorraine , Pusey Swerdzewski Barbara N. , Quinlan Aaron , Rao Deepak A. , Raper Anna , Raskind Wendy , Renteria Genecee , Reuter Chloe M. , Rives Lynette , Robertson Amy K. , Rodan Lance H. , Rosenfeld Jill A. , Rosenthal Elizabeth , Rossignol Francis , Ruzhnikov Maura , Sabaii Marla , Sampson Jacinda B. , Schedl Timothy , Schoch Kelly , Scott Daryl A. , Seto Elaine , Sharma Prashant , Shashi Vandana , Shelkowitz Emily , Sheppeard Sam , Shin Jimann , Silverman Edwin K. , Sinsheimer Janet S. , Sisco Kathy , Smith Kevin S. , Solnica-Krezel Lilianna , Solomon Ben , Spillmann Rebecca C. , Stergachis Andrew , Stoler Joan M. , Sullivan Kathleen , Sutton Shirley , Sweetser David A. , Sybert Virginia , Tabor Holly K. , Tan Queenie K.-G. , Tan Amelia L.M. , Tarakad Arjun , Taylor Herman , Tekin Mustafa , Thorson Willa , Tifft Cynthia J. , Toro Camilo , Tran Alyssa A. , Ungar Rachel A. , Urv Tiina K. , Vanderver Adeline , Velinder Matt , Viskochil Dave , Vogel Tiphanie P. , Wahl Colleen E. , Walker Melissa , Walley Nicole M. , Wambach Jennifer , Wan Jijun , Wang Lee-kai , Wangler Michael F. , Ward Patricia A. , Wegner Daniel , Hubshman Monika Weisz , Wener Mark , Wenger Tara , Westerfield Monte , Wheeler Matthew T. , Whitlock Jordan , Wolfe Lynne A. , Worley Kim , Yamamoto Shinya , Zhang Zhe , Zuchner Stephan , Liu Bo , Majer Olivia , Barton Gregory M. 
Published: May 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.