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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.


  1. 1.

    , , & IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).

  2. 2.

    & Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140, 845–858 (2010).

  3. 3.

    et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

  4. 4.

    et al. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORgammat function. Nature 453, 236–240 (2008).

  5. 5.

    , , & Cutting edge: regulatory T cells induce CD4+CD25Foxp3 T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-β. J. Immunol. 178, 6725–6729 (2007).

  6. 6.

    et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29, 44–56 (2008).

  7. 7.

    et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000–1007 (2009).

  8. 8.

    , & Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

  9. 9.

    et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science 309, 1074–1078 (2005).

  10. 10.

    et al. TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J. 19, 6778–6791 (2000).

  11. 11.

    & The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin. Cell Dev. Biol. 23, 785–793 (2012).

  12. 12.

    , & YAP/TAZ at the roots of cancer. Cancer Cell 29, 783–803 (2016).

  13. 13.

    et al. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat. Cell Biol. 10, 837–848 (2008).

  14. 14.

    et al. The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. Dev. Cell 19, 831–844 (2010).

  15. 15.

    , & Hippo Pathway in organ size control, tissue homeostasis, and cancer. Cell 163, 811–828 (2015).

  16. 16.

    The hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010).

  17. 17.

    , & The Hippo pathway and human cancer. Nat. Rev. Cancer 13, 246–257 (2013).

  18. 18.

    & The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat. Rev. Drug Discov. 13, 63–79 (2014).

  19. 19.

    , & Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat. Rev. Mol. Cell Biol. 13, 591–600 (2012).

  20. 20.

    et al. Protein kinases of the Hippo pathway: regulation and substrates. Semin. Cell Dev. Biol. 23, 770–784 (2012).

  21. 21.

    . et al. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood 119, 3458–3468 (2012).

  22. 22.

    et al. The phenotype of human STK4 deficiency. Blood 119, 3450–3457 (2012).

  23. 23.

    et al. The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naïve T cells. Proc. Natl. Acad. Sci. USA 105, 20321–20326 (2008).

  24. 24.

    , & Spatiotemporal regulation of the kinase Mst1 by binding protein RAPL is critical for lymphocyte polarity and adhesion. Nat. Immunol. 7, 919–928 (2006).

  25. 25.

    , , & RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nat. Immunol. 4, 741–748 (2003).

  26. 26.

    et al. Crucial functions of the Rap1 effector molecule RAPL in lymphocyte and dendritic cell trafficking. Nat. Immunol. 5, 1045–1051 (2004).

  27. 27.

    et al. Deficiency of Rap1-binding protein RAPL causes lymphoproliferative disorders through mislocalization of p27kip1. Immunity 34, 24–38 (2011).

  28. 28.

    et al. Mammalian sterile 20-like kinase 1 (Mst1) enhances the stability of Forkhead box P3 (Foxp3) and the function of regulatory T Cells by modulating Foxp3 acetylation. J. Biol. Chem. 290, 30762–30770 (2015).

  29. 29.

    et al. A cell-intrinsic role for Mst1 in regulating thymocyte egress. J. Immunol. 183, 3865–3872 (2009).

  30. 30.

    et al. Mst1/Mst2 regulate development and function of regulatory T cells through modulation of Foxo1/Foxo3 stability in autoimmune disease. J. Immunol. 192, 1525–1535 (2014).

  31. 31.

    et al. Mst1 controls lymphocyte trafficking and interstitial motility within lymph nodes. EMBO J. 28, 1319–1331 (2009).

  32. 32.

    et al. Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus. Nat. Commun. 3, 1098 (2012).

  33. 33.

    et al. Rab13 acts downstream of the kinase Mst1 to deliver the integrin LFA-1 to the cell surface for lymphocyte trafficking. Sci. Signal. 7, ra72 (2014).

  34. 34.

    et al. The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility. Sci. Signal. 8, ra100 (2015).

  35. 35.

    et al. The Hippo pathway knases LATS1/2 suppress cancer immunity. Cell 167, 1525–1539 (2016).

  36. 36.

    et al. Toll receptor-mediated Hippo signaling controls innate immunity in Drosophila. Cell 164, 406–419 (2016).

  37. 37.

    et al. Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nat. Immunol. 16, 1142–1152 (2015).

  38. 38.

    et al. The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes. J. Exp. Med. 209, 741–759 (2012).

  39. 39.

    et al. The kinase MST4 limits inflammatory responses through direct phosphorylation of the adaptor TRAF6. Nat. Immunol. 16, 246–257 (2015).

  40. 40.

    et al. T cell receptor “inside-out” pathway via signaling module SKAP1-RapL regulates T cell motility and interactions in lymph nodes. Immunity 32, 541–556 (2010).

  41. 41.

    et al. STK4 regulates TLR pathways and protects against chronic inflammation-related hepatocellular carcinoma. J. Clin. Invest. 125, 4239–4254 (2015).

  42. 42.

    et al. Single tumor-initiating cells evade immune clearance by recruiting type II macrophages. Genes Dev. 31, 247–259 (2017).

  43. 43.

    & Post-translational modification networks regulating FOXP3 function. Trends Immunol. 35, 368–378 (2014).

  44. 44.

    et al. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol. Cell. Biol. 28, 2426–2436 (2008).

  45. 45.

    et al. TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J. Biol. Chem. 284, 13355–13362 (2009).

  46. 46.

    et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell 158, 157–170 (2014).

  47. 47.

    , & Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nat. Immunol. 9, 1297–1306 (2008).

  48. 48.

    et al. T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nat. Immunol. 12, 96–104 (2011).

  49. 49.

    et al. SOCS3 regulates the plasticity of gp130 signaling. Nat. Immunol. 4, 546–550 (2003).

  50. 50.

    et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat. Immunol. 4, 540–545 (2003).

  51. 51.

    et al. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science 332, 687–696 (2011).

  52. 52.

    et al. viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat. Biotechnol. 31, 545–552 (2013).

  53. 53.

    et al. The Ets transcription factor GABP is a component of the hippo pathway essential for growth and antioxidant defense. Cell Rep. 3, 1663–1677 (2013).

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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.


  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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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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