The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells

• DOI: 10.1038/ni.3748
• Publication Date: 2017-05-15T15:01:00Z
• Authors: Jing Geng; Shujuan Yu; Hao Zhao; Xiufeng Sun; Xun Li; Ping Wang; Xiaolin Xiong; Lixin Hong; Changchuan Xie; Jiahui Gao; Yiran Shi; Jiaqi Peng; Randy L Johnson; Nengming Xiao; Linrong Lu; Jiahuai Han; Dawang Zhou; Lanfen Chen
• Keywords: 0301 basic medicine; 570; Chromatin Immunoprecipitation; Encephalomyelitis, Autoimmune, Experimental; Adaptive immunity; Immunoblotting; Autoimmunity; Lysine Acetyltransferase 5; Arthritis, Rheumatoid; 03 medical and health sciences; Animals; Humans; Adaptor Proteins, Signal Transducing; Histone Acetyltransferases; Intracellular Signaling Peptides and Proteins; Acetylation; Cell Differentiation; Forkhead Transcription Factors; Colitis; Flow Cytometry; DNA-Binding Proteins; Lymphocyte differentiation; HEK293 Cells; Case-Control Studies; Cytokines; HeLa Cells

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.