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 B.S. Briggs, Simon G. Gregory, Dennis C. Ko, William S. Fagg, Shelton Bradrick, Mariano A. Garcia-Blanco

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere76927
JournaleLife
Volume12
DOIs
StatePublished - Jun 2023

ASJC Scopus subject areas

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

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