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  • Title: The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate.
    Author: Hirano M, Galarza-Muñoz G, Nagasawa C, Schott G, Wang L, Antonia AL, Jain V, Yu X, Widen SG, Briggs FBS, Gregory SG, Ko DC, Fagg WS, Bradrick S, Garcia-Blanco MA.
    Journal: Elife; 2023 Jun 01; 12():. PubMed ID: 37261960.
    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.
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