title: Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice.
abstract: TANK-binding kinase 1 (TBK1) is a serine/threonine protein kinase that plays a crucial role in innate immunity. Enhanced TBK1 function is associated with autoimmune diseases and cancer, implicating the potential benefit of therapeutically targeting TBK1. In this article, we examined a recently identified TBK1 inhibitor Compound II on treating autoimmune diseases. We found that Compound II is a potent and specific inhibitor of TBK1-mediated IFN response. Compound II inhibited polyinosinic-polycytidylic acid-induced immune activation in vitro and in vivo. Compound II treatment also ameliorated autoimmune disease phenotypes of Trex1(-/-) mice, increased mouse survival, and dampened the IFN gene signature in TREX1 mutant patient lymphoblasts. In addition, we found that TBK1 gene expression is elevated in systemic lupus erythematosus patient cells, and systemic lupus erythematosus cells with high IFN signature responded well to Compound II treatment. Together, our findings provided critical experimental evidence for inhibiting TBK1 with Compound II as an effective treatment for TREX1-associated autoimmune diseases and potentially other interferonopathies.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Maroof
authors.identifier: http://orcid.org/0000-0003-4640-6949
authors.initials: M
authors.lastname: Hasan
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Nicole
authors.initials: N
authors.lastname: Dobbs
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Shaheen
authors.identifier: http://orcid.org/0000-0002-1472-8129
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Edward K
authors.identifier: http://orcid.org/0000-0002-7107-0992
authors.initials: EK
authors.lastname: Wakeland
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390; nan.yan@utsouthwestern.edu.
authors.forename: Nan
authors.initials: N
authors.lastname: Yan
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D002460:Cell Line; D005090:Exodeoxyribonucleases / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D007372:Interferons / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics; D011070:Poly I-C / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000378:metabolism
chemical_list: D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D007372:Interferons; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1; D011070:Poly I-C