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

Authors :
Minato Hirano
Gaddiel Galarza-Muñoz
Geraldine Schott
Liuyang Wang
Chloe Nagasawa
Alejandro L. Antonia
Vaibhav Jain
Xiaoying Yu
Steven G. Widen
Farren B.S. Briggs
Simon G. Gregory
Dennis C. Ko
W. Samuel Fagg
Shelton S. Bradrick
Mariano A. Garcia-Blanco
Publication Year :
2022
Publisher :
Cold Spring Harbor Laboratory, 2022.

Abstract

SummaryGenes 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 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 ForkheadBox 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 subclass 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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........58b2e9db8e6b695cb8caf4a9a811cecc