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

被引：17

作者：

Hirano, Minato ^{[1
,2
]}

Galarza-Munoz, Gaddiel ^{[1
,3
]}

Nagasawa, Chloe ^{[1
,4
]}

Schott, Geraldine ^{[1
]}

Wang, Liuyang ^{[5
]}

Antonia, Alejandro L. ^{[6
]}

Jain, Vaibhav ^{[7
]}

Yu, Xiaoying ^{[8
]}

Widen, Steven G.

Briggs, Farren B. S.

Gregory, Simon G. ^{[9
]}

Ko, Dennis C. ^{[10
]}

Fagg, William S. ^{[1
,11
]}

Bradrick, Shelton ^{[12
]}

Garcia-Blanco, Mariano A. ^{[1
,13
,14
]}

机构：

[1] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA

[2] Nagasaki Univ, Natl Res Ctr Control & Prevent Infect Dis, Nagasaki, Japan

[3] Autoimmun Biol Solut, Galveston, TX USA

[4] Univ Texas Med Branch, Inst Translat Sci, Human Pathophysiol & Translat Med Program, Galveston, TX USA

[5] Duke Univ, Dept Mol Genet & Microbiol, Durham, NC USA

[6] Duke Univ, Duke Mol Physiol Inst, Durham, NC USA

[7] Univ Texas Med Branch, Dept Prevent Med & Populat Hlth, Galveston, TX 77555 USA

[8] Case Western Reserve Univ, Sch Med, Dept Populat & Quantitat Hlth Sci, Cleveland, OH USA

[9] Duke Univ, Dept Neurol, Sch Med, Durham, NC USA

[10] Duke Univ, Dept Med, Div Infect Dis, Durham, NC USA

[11] Univ Texas Med Branch, Transplant Div, Dept Surg, Galveston, TX USA

[12] Univ Texas Med Branch, Inst Human Infect & Immun, Galveston, TX 77555 USA

[13] Univ Texas Med Branch, Dept Internal Med, Galveston, TX 77555 USA

[14] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22908 USA

来源：

ELIFE | 2023年 / 12卷

基金：

美国国家卫生研究院;

关键词：

RNA helicase; DDX39B; RNA splicing; multiple sclerosis; autoimmunity; FOXP3; Human; BIOCHEMICAL-CHARACTERIZATION; INTERLEUKIN-7; RECEPTOR; POLYPYRIMIDINE TRACT; PROTEIN; EXPORT; GENES; IDENTIFICATION; REQUIREMENT; ENTEROPATHY; GENERATION;

D O I：

10.7554/eLife.76927

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-alpha 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.

引用

页数：25

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