The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation

Dan Lu; Liang Liu; Xin Ji; Yanan Gao; Xi Chen; Yu Liu; Yang Liu; Xuyang Zhao; Yan Li; Yunqiao Li; Yan Jin; Yu Zhang; Michael A McNutt; Yuxin Yin

doi:10.1038/ni.3278

The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation

Nat Immunol. 2015 Dec;16(12):1263-73. doi: 10.1038/ni.3278. Epub 2015 Oct 19.

Authors

Dan Lu¹, Liang Liu^{1

2}, Xin Ji¹, Yanan Gao³, Xi Chen¹, Yu Liu¹, Yang Liu¹, Xuyang Zhao¹, Yan Li³, Yunqiao Li¹, Yan Jin¹, Yu Zhang³, Michael A McNutt¹, Yuxin Yin^{1

2

4}

Affiliations

¹ Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
² Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
³ Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
⁴ Peking-Tsinghua Center for Life Sciences, Peking University Health Science Center, Beijing, China.

PMID: 26479789
DOI: 10.1038/ni.3278

Abstract

Deregulation of the TH17 subset of helper T cells is closely linked with immunological disorders and inflammatory diseases. However, the mechanism by which TH17 cells are regulated remains elusive. Here we found that the phosphatase DUSP2 (PAC1) negatively regulated the development of TH17 cells. DUSP2 was directly associated with the signal transducer and transcription activator STAT3 and attenuated its activity through dephosphorylation of STAT3 at Tyr705 and Ser727. DUSP2-deficient mice exhibited severe susceptibility to experimental colitis, with enhanced differentiation of TH17 cells and secretion of proinflammatory cytokines. In clinical patients with ulcerative colitis, DUSP2 was downregulated by DNA methylation and was not induced during T cell activation. Our data demonstrate that DUSP2 is a true STAT3 phosphatase that modulates the development of TH17 cells in the autoimmune response and inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / immunology*
Cells, Cultured
Colitis / chemically induced
Colitis / genetics
Colitis / immunology
Colitis, Ulcerative / genetics
Colitis, Ulcerative / immunology
Colitis, Ulcerative / metabolism
Cytokines / immunology
Cytokines / metabolism
DNA Methylation / immunology
Dextran Sulfate
Dual Specificity Phosphatase 2 / deficiency
Dual Specificity Phosphatase 2 / genetics
Dual Specificity Phosphatase 2 / immunology*
Gene Expression Regulation / immunology
HEK293 Cells
Humans
Immunoblotting
Inflammation Mediators / immunology
Inflammation Mediators / metabolism
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation / immunology
Protein Binding / immunology
Reverse Transcriptase Polymerase Chain Reaction
STAT3 Transcription Factor / immunology*
STAT3 Transcription Factor / metabolism
Th17 Cells / immunology*
Th17 Cells / metabolism
Tyrosine / immunology
Tyrosine / metabolism

Substances

Cytokines
Inflammation Mediators
STAT3 Transcription Factor
Tyrosine
Dextran Sulfate
Dual Specificity Phosphatase 2
Dusp2 protein, mouse