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

doi:10.7554/eLife.76927

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 journal › Article › peer-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 language	English (US)
Journal	eLife
Volume	12
DOIs	https://doi.org/10.7554/eLife.76927
State	Published - Jun 1 2023

Keywords

DDX39B
FOXP3
RNA helicase
RNA splicing
autoimmunity
biochemistry
chemical biology
human
immunology
inflammation
multiple sclerosis

ASJC Scopus subject areas

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

Access to Document

10.7554/eLife.76927

Cite this

@article{5d8f1e8d70824ba1840988d3ddd83df3,

title = "The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate",

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.",

keywords = "DDX39B, FOXP3, RNA helicase, RNA splicing, autoimmunity, biochemistry, chemical biology, human, immunology, inflammation, multiple sclerosis",

author = "Minato Hirano and Gaddiel Galarza-Mu{\~n}oz and Chloe Nagasawa and Geraldine Schott and Liuyang Wang and Antonia, {Alejandro L.} and Vaibhav Jain and Xiaoying Yu and Widen, {Steven G.} and Briggs, {Farren B.S.} and Gregory, {Simon G.} and Ko, {Dennis C.} and Fagg, {William S.} and Shelton Bradrick and Garcia-Blanco, {Mariano A.}",

note = "Publisher Copyright: {\textcopyright} 2023, Hirano, Galarza-Mu{\~n}oz et al.",

year = "2023",

month = jun,

day = "1",

doi = "10.7554/eLife.76927",

language = "English (US)",

volume = "12",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd",

}

TY - JOUR

T1 - The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate

AU - Hirano, Minato

AU - Galarza-Muñoz, Gaddiel

AU - Nagasawa, Chloe

AU - Schott, Geraldine

AU - Wang, Liuyang

AU - Antonia, Alejandro L.

AU - Jain, Vaibhav

AU - Yu, Xiaoying

AU - Widen, Steven G.

AU - Briggs, Farren B.S.

AU - Gregory, Simon G.

AU - Ko, Dennis C.

AU - Fagg, William S.

AU - Bradrick, Shelton

AU - Garcia-Blanco, Mariano A.

PY - 2023/6/1

Y1 - 2023/6/1

N2 - 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.

AB - 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.

KW - DDX39B

KW - FOXP3

KW - RNA helicase

KW - RNA splicing

KW - autoimmunity

KW - biochemistry

KW - chemical biology

KW - human

KW - immunology

KW - inflammation

KW - multiple sclerosis

UR - http://www.scopus.com/inward/record.url?scp=85160968323&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85160968323&partnerID=8YFLogxK

U2 - 10.7554/eLife.76927

DO - 10.7554/eLife.76927

M3 - Article

C2 - 37261960

AN - SCOPUS:85160968323

SN - 2050-084X

VL - 12

JO - eLife

JF - eLife

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this