1. The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate
- Author
-
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, and Mariano A Garcia-Blanco
- Subjects
RNA helicase ,DDX39B ,RNA splicing ,multiple sclerosis ,autoimmunity ,FOXP3 ,Medicine ,Science ,Biology (General) ,QH301-705.5 - 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.
- Published
- 2023
- Full Text
- View/download PDF