The transcriptional coactivator TAZ regulates reciprocal differentiation of T H 17 cells and T reg cells

Nat Immunol. 2017 Jul;18(7):800-812. doi: 10.1038/ni.3748. Epub 2017 May 15.

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.

MeSH terms

  • Acetylation
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology*
  • Animals
  • Arthritis, Rheumatoid / immunology
  • Case-Control Studies
  • Cell Differentiation / immunology*
  • Chromatin Immunoprecipitation
  • Colitis / immunology*
  • Cytokines / immunology*
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Flow Cytometry
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Histone Acetyltransferases / metabolism
  • Humans
  • Immunoblotting
  • Intracellular Signaling Peptides and Proteins / immunology*
  • Lysine Acetyltransferase 5
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Real-Time Polymerase Chain Reaction
  • STAT3 Transcription Factor / immunology
  • STAT3 Transcription Factor / metabolism
  • Sjogren's Syndrome / immunology
  • Smad Proteins / immunology
  • Smad Proteins / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / immunology*
  • Trans-Activators / metabolism
  • Transcription Factors / immunology
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • STAT3 Transcription Factor
  • Smad Proteins
  • Tead1 protein, mouse
  • Trans-Activators
  • Transcription Factors
  • WWTR1 protein, human
  • Wwtr1 protein, mouse
  • Histone Acetyltransferases
  • Kat5 protein, mouse
  • Lysine Acetyltransferase 5
  • Proteasome Endopeptidase Complex