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- Title
The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate.
- Authors
Minato Hirano; Galarza-Muñoz, Gaddiel; Nagasawa, Chloe; Schott, Geraldine; Liuyang Wang; Antonia, Alejandro L.; Jain, Vaibhav; Xiaoying Yu; Widen, Steven G.; Briggs, Farren B. S.; Gregory, Simon G.; Ko, Dennis C.; Fagg, William S.; Bradrick, Shelton; Garcia-Blanco, Mariano A.
- 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-a 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.
- Subjects
REGULATORY T cells; RNA helicase; RNA splicing; EPISTASIS (Genetics); IMMUNOLOGICAL tolerance
- Publication
eLife, 2023, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.76927