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

• DOI: 10.1084/jem.20232005
• Publication Date: 2024-05-23T13:58:16Z
• Authors: Victoria E. Rael; Julian A. Yano; John P. Huizar; Leianna C. Slayden; Madeleine A. Weiss; Elizabeth A. Turc...; 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. Berns...; Matthew T. Wheeler; Robert A. Saxton; ; Maria T. Acosta; David R. Adams; Raquel L. Alvarez; Justin Alvey; Aimee Allworth; Ashley Andrews; Euan A. Ashley; Ben Afzali; Carlos A. Bacino; Guney Bademci; Ashok Balasubrama...; Dustin Baldridge; Jim Bale; Michael Bamshad; Deborah Barbouth; Pinar Bayrak-Toyd...; Anita Beck; Alan H. Beggs; Edward Behrens; Gill Bejerano; Hugo J. Bellen; Jimmy Bennett; Jonathan A. Berns...; Gerard T. Berry; Anna Bican; Stephanie Bivona; Elizabeth Blue; John Bohnsack; Devon Bonner; Lorenzo Botto; Lauren C. Briere; Gabrielle Brown; Elizabeth A. Burke; Lindsay C. Burrage; Manish J. Butte; Peter Byers; William E. Byrd; John Carey; Thomas Cassini; Sirisak Chanprasert; Hsiao-Tuan Chao; Ivan Chinn; Gary D. Clark; Terra R. Coakley; Laurel A. Cobban; Joy D. Cogan; Matthew Coggins; F. Sessions Cole; Heather A. Colley; Rosario Corona; William J. Craigen; Andrew B. Crouse; Michael Cunningham; Precilla D’Souza; Hongzheng Dai; Surendra Dasari; Joie Davis; Jyoti G. Dayal; Margaret Delgado; Esteban C. Dell’A...; Katrina Dipple; Daniel Doherty; Naghmeh Dorrani; Argenia L. Doss; Emilie D. Douine; Dawn Earl; David J. Eckstein; Lisa T. Emrick; Christine M. Eng; Marni Falk; Elizabeth L. Fieg; Paul G. Fisher; Brent L. Fogel; Jiayu Fu; William A. Gahl; Ian Glass; Page C. Goddard; Rena A. Godfrey; Andrea Gropman; Meghan C. Halley; Rizwan Hamid; Neal Hanchard; Kelly Hassey; Nichole Hayes; Frances High; Anne Hing; Fuki M. Hisama; Ingrid A. Holm; Jason Hom; Martha Horike-Pyne; Alden Huang; Yan Huang; Sarah Hutchison; Wendy Introne; Kosuke Izumi; Gail P. Jarvik; Jeffrey Jarvik; Suman Jayadev; Orpa Jean-Marie; Vaidehi Jobanputra; Emerald Kaitryn; Shamika Ketkar; Dana Kiley; Gonench Kilich; Shilpa N. Kobren; Isaac S. Kohane; Jennefer N. Kohler; Susan Korrick; Deborah Krakow; Donna M. Krasnewich; Elijah Kravets; Seema R. Lalani; Christina Lam; Brendan C. Lanpher; Ian R. Lanza; Kimberly LeBlanc; Brendan H. Lee; Richard A. Lewis; Pengfei Liu; Nicola Longo; Sandra K. Loo; Joseph Loscalzo; Richard L. Maas; Ellen F. Macnamara; Calum A. MacRae; Valerie V. Maduro; AudreyStephannie ...; Rachel Mahoney; May Christine V. ...; Laura A. Mamounas; Teri A. Manolio; Rong Mao; Ronit Marom; Gabor Marth; Beth A. Martin; Martin G. Martin; Julian A. Martíne...; Shruti Marwaha; Allyn McConkie-Ro...; Alexa T. McCray; Elisabeth McGee; Matthew Might; Mohamad Mikati; Danny Miller; Ghayda Mirzaa; Eva Morava; Paolo Moretti; Marie Morimoto; John J. Mulvihill; Mariko Nakano-Okuno; Stanley F. Nelson; Shirley Nieves-Ro...; Donna Novacic; Devin Oglesbee; James P. Orengo; Laura Pace; Stephen Pak; J. Carl Pallais; Jeanette C. Papp; Neil H. Parker; Leoyklang Petcharet; John A. Phillips; Jennifer E. Posey; Lorraine Potocki; Barbara N. Pusey ...; Aaron Quinlan; Deepak A. Rao; Anna Raper; Wendy Raskind; Genecee Renteria; Chloe M. Reuter; Lynette Rives; Amy K. Robertson; Lance H. Rodan; Jill A. Rosenfeld; Elizabeth Rosenthal; Francis Rossignol; Maura Ruzhnikov; Marla Sabaii; Jacinda B. Sampson; Timothy Schedl; Kelly Schoch; Daryl A. Scott; Elaine Seto; Prashant Sharma; Vandana Shashi; Emily Shelkowitz; Sam Sheppeard; Jimann Shin; Edwin K. Silverman; Janet S. Sinsheimer; Kathy Sisco; Kevin S. Smith; Lilianna Solnica-...; Ben Solomon; Rebecca C. Spillmann; Andrew Stergachis; Joan M. Stoler; Kathleen Sullivan; Shirley Sutton; David A. Sweetser; Virginia Sybert; Holly K. Tabor; Queenie K.-G. Tan; Amelia L.M. Tan; Arjun Tarakad; Herman Taylor; Mustafa Tekin; Willa Thorson; Cynthia J. Tifft; Camilo Toro; Alyssa A. Tran; Rachel A. Ungar; Tiina K. Urv; Adeline Vanderver; Matt Velinder; Dave Viskochil; Tiphanie P. Vogel; Colleen E. Wahl; Melissa Walker; Nicole M. Walley; Jennifer Wambach; Jijun Wan; Lee-kai Wang; Michael F. Wangler; Patricia A. Ward; Daniel Wegner; Monika Weisz Hubs...; Mark Wener; Tara Wenger; Monte Westerfield; Matthew T. Wheeler; Jordan Whitlock; Lynne A. Wolfe; Kim Worley; Shinya Yamamoto; Zhe Zhang; Stephan Zuchner; Bo Liu; Olivia Majer; Gregory M. Barton
• Keywords: Male; 0301 basic medicine; DNA Mutational Analysis; Toll-Like Receptors; Membrane Transport Proteins; Autoimmunity; Article; Autoimmune Diseases; Mice, Inbred C57BL; Mice; 03 medical and health sciences; HEK293 Cells; Toll-Like Receptor 7; Mutation; Animals; Humans; Female

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.