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Abstract

An imbalance in the lineages of immunosuppressive regulatory T cells (Treg cells) and the inflammatory TH17 subset of helper T cells leads to the development of autoimmune and/or inflammatory disease. Here we found that TAZ, a coactivator of TEAD transcription factors of Hippo signaling, was expressed under TH17 cell–inducing conditions and was required for TH17 differentiation and TH17 cell–mediated inflammatory diseases. TAZ was a critical co-activator of the TH17-defining transcription factor RORγt. In addition, TAZ attenuated Treg cell development by decreasing acetylation of the Treg cell master regulator Foxp3 mediated by the histone acetyltransferase Tip60, which targeted Foxp3 for proteasomal degradation. In contrast, under Treg cell–skewing conditions, TEAD1 expression and sequestration of TAZ from the transcription factors RORγt and Foxp3 promoted Treg cell differentiation. Furthermore, deficiency in TAZ or overexpression of TEAD1 induced Treg cell differentiation, whereas expression of a transgene encoding TAZ or activation of TAZ directed TH17 cell differentiation. Our results demonstrate a pivotal role for TAZ in regulating the differentiation of Treg cells and TH17 cells.

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Change history

  • 20 July 2017

    In the version of this article initially published, the description of Figure 1d,e in the first subsection of Results was incorrect; "...(Lck-Cre): Tazfl/flLck-Cre mice) immunized with KLH exhibited a larger TH17 population and fewer Treg cells than that of their Tazfl/fl littermates..." should read: "...(Lck-Cre)): Tazfl/flLck-Cre mice immunized with KLH exhibited a smaller TH17 population and more Treg cells than that of their Tazfl/fl littermates...". Also, the second sentence of the panel legend for Figure 1a incorrectly identified the numbers in the plots on the top row as "percent TH7 cells..."; this should read "percent TH17 cells...". These errors have been corrected in the PDF and HTML versions of this article.

  • 14 February 2018

    In the version of this article initially published, the institution name for affiliation 3 (Maryland Anderson Cancer Center) was incorrect. The correct institution is MD Anderson Cancer Center. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank J. Avruch for comments on the manuscript. Supported by the National Basic Research Program (973) of China (2015CB910502 to L.C.), the National Natural Science Foundation of China (81422018 to L.C.; 31625010 and U1505224 to D.Z.; U1405225 and 81372617 to L.C.; J1310027 to D.Z.; 81472229 to L.H.; and 31600698 to J. Geng), the 111 Projects (B12001 and B06016), China's 1000 Young Talents Program (D.Z., and L.C.), the Fundamental Research Funds for the Central Universities of China-Xiamen University (20720160071 to D.Z. and 20720160054 to L.H.) and Major disease research projects of Xiamen (3502Z20149029 to L.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

    • Jing Geng
    • , Shujuan Yu
    • , Hao Zhao
    •  & Xiufeng Sun

    These authors contributed equally to this work.

Affiliations

  1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.

    • Jing Geng
    • , Shujuan Yu
    • , Hao Zhao
    • , Xiufeng Sun
    • , Ping Wang
    • , Xiaolin Xiong
    • , Lixin Hong
    • , Changchuan Xie
    • , Jiahui Gao
    • , Yiran Shi
    • , Jiaqi Peng
    • , Nengming Xiao
    • , Jiahuai Han
    • , Dawang Zhou
    •  & Lanfen Chen
  2. Department of Laboratory Medicine, the First Affiliated Hospital, Medical College of Xiamen University, Xiamen, China.

    • Xun Li
  3. Department of Cancer Biology, MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.

    • Randy L Johnson
  4. Institute of Immunology, Innovation Center for Cell Signaling Network, Zhejiang University School of Medicine, Hangzhou, China.

    • Linrong Lu
  5. Zhejiang University–University of Edinburgh Institute, Zhejiang University School of Medicine, Hangzhou, China.

    • Linrong Lu

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Contributions

J. Geng, S.Y., H.Z., X.S., P.W., X.X., L.H., J. Gao, Y.S. and J.P. performed experimental biological research; X.L. provided human blood samples; C.X. performed mass-spectrometry analysis; R.L.J. provided mutant mice; D.Z. and L.C. conceived of the project, with input from R.L.J., N.X., L.L. and J.H., co-wrote the paper; and all authors edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Dawang Zhou or Lanfen Chen.

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    Supplementary Text and Figures

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    Supplementary Dataset 1

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DOI

https://doi.org/10.1038/ni.3748

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