Reversing SKI-SMAD4-mediated suppression is essential for TH 17 cell differentiation

Nature
Song ZhangYisong Y Wan

Abstract

T helper 17 (TH17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor β (TGFβ) is instrumental in TH17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables TH17 cell differentiation remains elusive. Here we reveal that TGFβ enables TH17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH17 cell differentiation in a SMAD4-dependen...Continue Reading

References

Oct 27, 1999·Proceedings of the National Academy of Sciences of the United States of America·Y SunR A Weinberg
Feb 22, 2002·Genesis : the Journal of Genetics and Development·Anna ChytilHarold L Moses
Jun 15, 2005·Journal of Proteome Research·Tianyi WangXian Chen
Nov 30, 2005·The Journal of Experimental Medicine·Miriam Shapiro-ShelefKathryn Calame
Jan 5, 2007·Annual Review of Immunology·Casey T WeaverLaurie E Harrington
Feb 6, 2007·The Journal of Biological Chemistry·Xuexian O YangChen Dong
Mar 17, 2007·Immunity·Arian LaurenceJohn J O'shea
Dec 31, 2008·Cell Research·Julien Deheuninck, Kunxin Luo
Jan 10, 2009·Annual Review of Immunology·Thomas KornVijay K Kuchroo
Aug 28, 2009·The New England Journal of Medicine·Pierre MiossecVijay K Kuchroo
Sep 21, 2012·Nature Reviews. Molecular Cell Biology·Joan Massagué
Aug 26, 2014·Autoimmunity Reviews·Ram Pyare SinghAwlad Hossain
Sep 30, 2014·Cell·Randall J PlattFeng Zhang
Dec 20, 2015·Immunity·Dhavalkumar D Patel, Vijay K Kuchroo
May 18, 2016·Nucleic Acids Research·Kornel LabunEivind Valen

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Citations

Dec 9, 2017·Cell Research·Hao Xu, Dan R Littman
Dec 30, 2018·Proceedings of the National Academy of Sciences of the United States of America·Qin XuLinrong Lu
Jun 25, 2019·Expert Opinion on Therapeutic Targets·Hendrik Ungefroren
Nov 9, 2018·Oncology Letters·Jayra Juliana Paiva AlvesJosé Veríssimo Fernandes
Aug 31, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Chang-Sheng ZhanChao-Zhao Liang
Jun 13, 2018·Cancers·Amina Dahmani, Jean-Sébastien Delisle
Mar 23, 2018·Cellular & Molecular Immunology·Hannah M KnochelmannChrystal M Paulos
Mar 21, 2019·Seminars in Immunopathology·Yuya HagiharaTakanori Kanai
May 18, 2020·Cell Death & Disease·Xing DuQifa Li
Jul 1, 2020·PLoS Genetics·Manuel A R FerreiraGerard H Koppelman
Aug 7, 2019·Annual Review of Pharmacology and Toxicology·Anton M Jetten, Donald N Cook
Jul 18, 2020·Frontiers in Immunology·Mengjuan Zhang, Song Zhang
Jun 19, 2018·Frontiers in Immunology·Tanbeena ImamMatthew R Olson
May 6, 2020·International Journal of Nanomedicine·Guilan ZhangLongquan Shao
Jul 6, 2020·Nature Communications·Hao XuNicola Gagliani
Jul 3, 2020·Cellular & Molecular Immunology·Bing WuYisong Y Wan
Aug 23, 2020·Immunologic Research·Binbin LiWeirong Fang
Feb 18, 2021·Proceedings of the National Academy of Sciences of the United States of America·Ekin BolukbasiLinda Partridge
Dec 12, 2020·Laboratory Investigation; a Journal of Technical Methods and Pathology·Yue WangYuan Li
Feb 23, 2020·Immunity·Sharon S Evans, Michelle M Appenheimer
Aug 6, 2019·Current Opinion in Cell Biology·Yi Yu, Xin-Hua Feng
Apr 6, 2021·Journal of Immunology Research·Kailei Guo, Xiaomin Zhang
Apr 24, 2021·OncoTargets and Therapy·Rongxue WanLiling Tang
May 21, 2021·Frontiers in Immunology·Hamid R RazzaghianPascal M Lavoie
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Haozhen MaFang Huang
Jun 22, 2021·International Reviews of Immunology·Kevin M HarrisLinda R Watkins
Sep 3, 2021·The Journal of Experimental Medicine·Hao XuDan R Littman
Aug 1, 2020·The American Journal of Pathology·Michel E MickaelRajatava Basu

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Datasets Mentioned

BETA
PXD007172
GSE101593
GSE101527

Methods Mentioned

BETA
histone acetylation
acetylation
PMA
flow-cytometry
PCR
ChIP-seq
RNA-seq
ChIP

Software Mentioned

STAR
Andromeda
CHOPCHOP
Bowtie1
DESeq2
Trim Galore
Bioconductor
XCalibur

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