The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate

Author:

Hirano Minato12,Galarza-Muñoz Gaddiel13,Nagasawa Chloe14,Schott Geraldine1,Wang Liuyang5,Antonia Alejandro L5,Jain Vaibhav6,Yu Xiaoying17,Widen Steven G1ORCID,Briggs Farren BS8,Gregory Simon G569,Ko Dennis C510ORCID,Fagg William S111,Bradrick Shelton12ORCID,Garcia-Blanco Mariano A11314ORCID

Affiliation:

1. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch

2. National Research Center for the Control and Prevention of Infectious Disease, Nagasaki University

3. Autoimmunity Biological Solutions

4. Human Pathophysiology and Translational Medicine Program, Institute for Translational Sciences, University of Texas Medical Branch

5. Department of Molecular Genetics and Microbiology, Duke University

6. Duke Molecular Physiology Institute, Duke University

7. Department of Preventive Medicine and Population Health, University of Texas Medical Branch

8. Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University

9. Department of Neurology, Duke University School of Medicine

10. Division of Infectious Diseases, Department of Medicine, Duke University

11. Transplant Division, Department of Surgery, University of Texas Medical Branch

12. Institute of Human Infections and Immunity, University of Texas Medical Branch

13. Department of Internal Medicine, University of Texas Medical Branch

14. Department of Microbiology, Immunology and Cancer Biology, University of Virginia

Abstract

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.

Funder

Uehara Foundation

McLaughlin Family Foundation

National Institutes of Health

Stone Family Fund

National Cancer Institute

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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