Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | e20232005 |
| Journal | Journal of Experimental Medicine |
| Volume | 221 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 5 2024 |
Keywords
- Autoimmunity
- Human disease genetics
- Innate immunity and inflammation
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
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In: Journal of Experimental Medicine, Vol. 221, No. 8, e20232005, 05.08.2024.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Large-Scale Mutational Analysis Identifies UNC93B1 Variants that Drive TLR-Mediated Autoimmunity in Mice and Humans
AU - Rael, Victoria E.
AU - Yano, Julian A.
AU - Huizar, John P.
AU - Slayden, Leianna C.
AU - Weiss, Madeleine A.
AU - Turcotte, Elizabeth A.
AU - Terry, Jacob M.
AU - Zuo, Wenqi
AU - Thiffault, Isabelle
AU - Pastinen, Tomi
AU - Farrow, Emily G.
AU - Jenkins, Janda L.
AU - Becker, Mara L.
AU - Wong, Stephen C.
AU - Stevens, Anne M.
AU - Otten, Catherine
AU - Allenspach, Eric J.
AU - Bonner, Devon E.
AU - Bernstein, Jonathan A.
AU - Wheeler, Matthew T.
AU - Saxton, Robert A.
AU - Liu, Bo
AU - Majer, Olivia
AU - Barton, Gregory M.
AU - Acosta, Maria T.
AU - Adams, David R.
AU - Alvarez, Raquel L.
AU - Alvey, Justin
AU - Allworth, Aimee
AU - Andrews, Ashley
AU - Ashley, Euan A.
AU - Afzali, Ben
AU - Bacino, Carlos A.
AU - Bademci, Guney
AU - Balasubramanyam, Ashok
AU - Baldridge, Dustin
AU - Bale, Jim
AU - Bamshad, Michael
AU - Barbouth, Deborah
AU - Bayrak-Toydemir, Pinar
AU - Beck, Anita
AU - Beggs, Alan H.
AU - Behrens, Edward
AU - Bejerano, Gill
AU - Bellen, Hugo J.
AU - Bennett, Jimmy
AU - Bernstein, Jonathan A.
AU - Berry, Gerard T.
AU - Bican, Anna
AU - Bivona, Stephanie
AU - Blue, Elizabeth
AU - Bohnsack, John
AU - Bonner, Devon
AU - Botto, Lorenzo
AU - Briere, Lauren C.
AU - Brown, Gabrielle
AU - Burke, Elizabeth A.
AU - Burrage, Lindsay C.
AU - Butte, Manish J.
AU - Byers, Peter
AU - Byrd, William E.
AU - Carey, John
AU - Cassini, Thomas
AU - Chanprasert, Sirisak
AU - Chao, Hsiao Tuan
AU - Chinn, Ivan
AU - Clark, Gary D.
AU - Coakley, Terra R.
AU - Cobban, Laurel A.
AU - Cogan, Joy D.
AU - Coggins, Matthew
AU - Sessions Cole, F.
AU - Colley, Heather A.
AU - Corona, Rosario
AU - Craigen, William J.
AU - Crouse, Andrew B.
AU - Cunningham, Michael
AU - D’souza, Precilla
AU - Dai, Hongzheng
AU - Dasari, Surendra
AU - Davis, Joie
AU - Dayal, Jyoti G.
AU - Delgado, Margaret
AU - Dell’angelica, Esteban C.
AU - Dipple, Katrina
AU - Doherty, Daniel
AU - Dorrani, Naghmeh
AU - Doss, Argenia L.
AU - Douine, Emilie D.
AU - Earl, Dawn
AU - Eckstein, David J.
AU - Emrick, Lisa T.
AU - Eng, Christine M.
AU - Falk, Marni
AU - Fieg, Elizabeth L.
AU - Fisher, Paul G.
AU - Fogel, Brent L.
AU - Fu, Jiayu
AU - Gahl, William A.
AU - Glass, Ian
AU - Goddard, Page C.
AU - Godfrey, Rena A.
AU - Gropman, Andrea
AU - Halley, Meghan C.
AU - Hamid, Rizwan
AU - Hanchard, Neal
AU - Hassey, Kelly
AU - Hayes, Nichole
AU - High, Frances
AU - Hing, Anne
AU - Hisama, Fuki M.
AU - Holm, Ingrid A.
AU - Hom, Jason
AU - Horike-Pyne, Martha
AU - Huang, Alden
AU - Huang, Yan
AU - Hutchison, Sarah
AU - Introne, Wendy
AU - Izumi, Kosuke
AU - Jarvik, Gail P.
AU - Jarvik, Jeffrey
AU - Jayadev, Suman
AU - Jean-Marie, Orpa
AU - Jobanputra, Vaidehi
AU - Kaitryn, Emerald
AU - Ketkar, Shamika
AU - Kiley, Dana
AU - Kilich, Gonench
AU - Kobren, Shilpa N.
AU - Kohane, Isaac S.
AU - Kohler, Jennefer N.
AU - Korrick, Susan
AU - Krakow, Deborah
AU - Krasnewich, Donna M.
AU - Kravets, Elijah
AU - Lalani, Seema R.
AU - Lam, Christina
AU - Lanpher, Brendan C.
AU - Lanza, Ian R.
AU - Leblanc, Kimberly
AU - Lee, Brendan H.
AU - Lewis, Richard A.
AU - Liu, Pengfei
AU - Longo, Nicola
AU - Loo, Sandra K.
AU - Loscalzo, Joseph
AU - Maas, Richard L.
AU - Macnamara, Ellen F.
AU - Macrae, Calum A.
AU - Maduro, Valerie V.
AU - Maghiro, Audrey Stephannie
AU - Mahoney, Rachel
AU - Malicdan, May Christine V.
AU - Mamounas, Laura A.
AU - Manolio, Teri A.
AU - Mao, Rong
AU - Marom, Ronit
AU - Marth, Gabor
AU - Martin, Beth A.
AU - Martin, Martin G.
AU - Martínez-Agosto, Julian A.
AU - Marwaha, Shruti
AU - McConkie-Rosell, Allyn
AU - McCray, Alexa T.
AU - McGee, Elisabeth
AU - Might, Matthew
AU - Mikati, Mohamad
AU - Miller, Danny
AU - Mirzaa, Ghayda
AU - Morava, Eva
AU - Moretti, Paolo
AU - Morimoto, Marie
AU - Mulvihill, John J.
AU - Nakano-Okuno, Mariko
AU - Nelson, Stanley F.
AU - Nieves-Rodriguez, Shirley
AU - Novacic, Donna
AU - Oglesbee, Devin
AU - Orengo, James P.
AU - Pace, Laura
AU - Pak, Stephen
AU - Carl Pallais, J.
AU - Papp, Jeanette C.
AU - Parker, Neil H.
AU - Petcharet, Leoyklang
AU - Phillips, John A.
AU - Posey, Jennifer E.
AU - Potocki, Lorraine
AU - Pusey, Barbara N.
AU - Swerdzewski,
AU - Quinlan, Aaron
AU - Rao, Deepak A.
AU - Raper, Anna
AU - Raskind, Wendy
AU - Renteria, Genecee
AU - Reuter, Chloe M.
AU - Rives, Lynette
AU - Robertson, Amy K.
AU - Rodan, Lance H.
AU - Rosenfeld, Jill A.
AU - Rosenthal, Elizabeth
AU - Rossignol, Francis
AU - Ruzhnikov, Maura
AU - Sabaii, Marla
AU - Sampson, Jacinda B.
AU - Schedl, Timothy
AU - Schoch, Kelly
AU - Scott, Daryl A.
AU - Seto, Elaine
AU - Sharma, Prashant
AU - Shashi, Vandana
AU - Shelkowitz, Emily
AU - Sheppeard, Sam
AU - Shin, Jimann
AU - Silverman, Edwin K.
AU - Sinsheimer, Janet S.
AU - Sisco, Kathy
AU - Smith, Kevin S.
AU - Solnica-Krezel, Lilianna
AU - Solomon, Ben
AU - Spillmann, Rebecca C.
AU - Stergachis, Andrew
AU - Stoler, Joan M.
AU - Sullivan, Kathleen
AU - Sutton, Shirley
AU - Sweetser, David A.
AU - Sybert, Virginia
AU - Tabor, Holly K.
AU - Tan, Queenie K.G.
AU - Tan, Amelia L.M.
AU - Tarakad, Arjun
AU - Taylor, Herman
AU - Tekin, Mustafa
AU - Thorson, Willa
AU - Tifft, Cynthia J.
AU - Toro, Camilo
AU - Tran, Alyssa A.
AU - Ungar, Rachel A.
AU - Urv, Tiina K.
AU - Vanderver, Adeline
AU - Velinder, Matt
AU - Viskochil, Dave
AU - Vogel, Tiphanie P.
AU - Wahl, Colleen E.
AU - Walker, Melissa
AU - Walley, Nicole M.
AU - Wambach, Jennifer
AU - Wan, Jijun
AU - Wang, Lee Kai
AU - Wangler, Michael F.
AU - Ward, Patricia A.
AU - Wegner, Daniel
AU - Hubshman, Monika Weisz
AU - Wener, Mark
AU - Wenger, Tara
AU - Westerfield, Monte
AU - Wheeler, Matthew T.
AU - Whitlock, Jordan
AU - Wolfe, Lynne A.
AU - Worley, Kim
AU - Yamamoto, Shinya
AU - Zhang, Zhe
AU - Zuchner, Stephan
N1 - Publisher Copyright: © 2024 Rael et al.
PY - 2024/8/5
Y1 - 2024/8/5
N2 - 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.
AB - 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.
KW - Autoimmunity
KW - Human disease genetics
KW - Innate immunity and inflammation
UR - http://www.scopus.com/inward/record.url?scp=85194026405&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85194026405&partnerID=8YFLogxK
U2 - 10.1084/jem.20232005
DO - 10.1084/jem.20232005
M3 - Article
C2 - 38780621
AN - SCOPUS:85194026405
SN - 0022-1007
VL - 221
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 8
M1 - e20232005
ER -