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

2024; Rockefeller University Press; Volume: 221; Issue: 8 Linguagem: Inglês

10.1084/jem.20232005

1540-9538

Victoria E. Rael, Julian A. Yano, John Huizar, Leianna C. Slayden, Madeleine A. Weiss, Elizabeth A. Turcotte, J M Terry, Wenqi Zuo, Isabelle Thiffault, Tomi Pastinen, Emily Farrow, Janda Jenkins, Mara L. Becker, Stephen C. Wong, Anne M. Stevens, Catherine Otten, Eric J. Allenspach, Devon Bonner, Jonathan A. Bernstein, 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, Güney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael J. Bamshad, Deborah Barbouth, Pınar Bayrak‐Toydemir, Anita Beck, Alan H. Beggs, Edward M. Behrens, Gill Bejerano, Hugo J. Bellen, Jimmy Bennett, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Devon Bonner, Lorenzo D. Botto, Lauren C. Briere, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter H. Byers, William E. Byrd, John M. Carey, Thomas Cassini, Sirisak Chanprasert, Hsiao‐Tuan Chao, Iván K. Chinn, Gary Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Rosario I. Corona, William J. Craigen, Andrew B. Crouse, Michael L. Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Margaret Delgado, Esteban C. Dell’Angelica, Katrina M. Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, Dawn Earl, David J. Eckstein, Lisa Emrick, Christine M. Eng, Marni J. Falk, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Jiayu Fu, William A. Gahl, I. S. Glass, Pagé C. Goddard, Rena A. Godfrey, Andrea Gropman, Meghan C. Halley, Rizwan Hamid, Neal Hanchard, Kelly Hassey, Nichole Hayes, Frances A. High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike‐Pyne, Alden Huang, Yan Huang, Sarah Hutchison, Wendy J. Introne, Kosuke Izumi, Gail P. Jarvik, Jeffrey G. 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 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 Maghiro, Rachel Mahoney, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Ronit Marom, Gábor Marth, Beth A. Martin, Martin G. Martin, Julián A. Martínez-Agosto, Shruti Marwaha, Allyn McConkie‐Rosell, Alexa T. McCray, Elisabeth McGee, Matthew Might, Mohamad A. Mikati, Danny E. Miller, Ghayda Mirzaa, Éva Morava, Paolo Moretti, Marie Morimoto, John J. Mulvihill, Mariko Nakano‐Okuno, Stanley F. Nelson, Shirley Nieves‐Rodriguez, 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 Swerdzewski, Aaron R. Quinlan, Deepak A. Rao, Anna Raper, Wendy H. Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Elizabeth M. 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‐Krezel, Ben Solomon, Rebecca C. Spillmann, Andrew B. Stergachis, Joan M. Stoler, Kathleen E. Sullivan, Shirley Sutton, David A. Sweetser, Virginia P. Sybert, Holly K. Tabor, Queenie K.‐G. Tan, Amelia L.M. Tan, Arjun Tarakad, Herman A. 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, Sophie Nicole, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Monika Weisz Hubshman, Mark H. Wener, Tara Wenger, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Kim C. Worley, Shinya Yamamoto, Zhe Zhang, Stephan Züchner, Bo Liu, Olivia Majer, Gregory M. Barton,

Immunotherapy and Immune Responses

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.