The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate
Minato Hirano,
Gaddiel Galarza-Muñoz,
Chloe Nagasawa,
Geraldine Schott,
Liuyang Wang,
Alejandro L Antonia,
Vaibhav Jain,
Xiaoying Yu,
Steven G Widen,
Farren BS Briggs,
Simon G Gregory,
Dennis C Ko,
William S Fagg,
Shelton Bradrick,
Mariano A Garcia-Blanco
Affiliations
Minato Hirano
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, United States; National Research Center for the Control and Prevention of Infectious Disease, Nagasaki University, Nagasaki, Japan
Gaddiel Galarza-Muñoz
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, United States; Autoimmunity Biological Solutions, Galveston, United States
Chloe Nagasawa
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, United States; Human Pathophysiology and Translational Medicine Program, Institute for Translational Sciences, University of Texas Medical Branch, Galveston, United States
Geraldine Schott
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, United States
Liuyang Wang
Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
Alejandro L Antonia
Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
Vaibhav Jain
Duke Molecular Physiology Institute, Duke University, Durham, United States
Xiaoying Yu
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, United States; Department of Preventive Medicine and Population Health, University of Texas Medical Branch, Galveston, United States
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, United States
Farren BS Briggs
Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, United States
Simon G Gregory
Department of Molecular Genetics and Microbiology, Duke University, Durham, United States; Duke Molecular Physiology Institute, Duke University, Durham, United States; Department of Neurology, Duke University School of Medicine, Durham, United States
Department of Molecular Genetics and Microbiology, Duke University, Durham, United States; Division of Infectious Diseases, Department of Medicine, Duke University, Durham, United States
William S Fagg
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, United States; Transplant Division, Department of Surgery, University of Texas Medical Branch, Galveston, United States
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, United States; Department of Internal Medicine, University of Texas Medical Branch, Galveston, United States; Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, United States
Genes associated with increased susceptibility to multiple sclerosis (MS) have been identified, but their functions are incompletely understood. One of these genes codes for the RNA helicase DExD/H-Box Polypeptide 39B (DDX39B), which shows genetic and functional epistasis with interleukin-7 receptor-α gene (IL7R) in MS-risk. Based on evolutionary and functional arguments, we postulated that DDX39B enhances immune tolerance thereby decreasing MS risk. Consistent with such a role we show that DDX39B controls the expression of many MS susceptibility genes and important immune-related genes. Among these we identified Forkhead Box P3 (FOXP3), which codes for the master transcriptional factor in CD4+/CD25+ T regulatory cells. DDX39B knockdown led to loss of immune-regulatory and gain of immune-effector expression signatures. Splicing of FOXP3 introns, which belong to a previously unrecognized type of introns with C-rich polypyrimidine tracts, was exquisitely sensitive to DDX39B levels. Given the importance of FOXP3 in autoimmunity, this work cements DDX39B as an important guardian of immune tolerance.
