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

Geng, Jing; Yu, Shujuan; Zhao, Hao; Sun, Xiulian; Li, Xun; Wang, Ping; Xiong, Xiaolin; Hong, Lian; Xie, Changchuan; Gao, Jiahui; Shi, Yiran; Peng, Jiaqi; Johnson, Randy L.; Xiao, Nengming; Lu, Linrong; Han, Jiahuai; Zhou, Dawang; Chen, Lanfen

doi:10.1038/ni.3748

Cited by 166 publications

(158 citation statements)

References 54 publications

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“…Despite these potential mechanistic risks for AI/I development, 4 AI/I are not widely reported in Barth syndrome patients. Recently TAZ has been described to regulate Th17 and Treg development, and TAZ ‐deficient lymphocytes show impaired Th17 and increased Treg differentiation 38 . This lymphocyte defect may protect Barth syndrome patients from AI/I disease.…”

Section: Discussionmentioning

confidence: 98%

Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

et al. 2017

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Primary immunodeficiencies (PIDs) are rare inborn errors of immunity that have a heterogeneous phenotype that can include severe susceptibility to life-threatening infections from multiple pathogens, unique sensitivity to a single pathogen, autoimmune/inflammatory (AI/I) disease, allergies and/or malignancy. We present a diverse cohort of monogenic PID patients with and without AI/I diseases who underwent clinical, genetic and immunological phenotyping. Novel pathogenic variants were identified in IKBKG, CTLA4, NFKB1, GATA2, CD40LG and TAZ as well as previously reported pathogenic variants in STAT3, PIK3CD, STAT1, NFKB2 and STXBP2. AI/I manifestations were frequently encountered in PIDs, including at presentation. Autoimmunity/inflammation was multisystem in those effected, and regulatory T cell (Treg) percentages were significantly decreased compared with those without AI/I manifestations. Prednisolone was used as the first-line immunosuppressive agent in all cases, however steroid monotherapy failed long-term control of autoimmunity/inflammation in the majority of cases and additional immunosuppression was required. Patients with multisystem autoimmunity/inflammation should be investigated for an underlying PID, and in those with PID early assessment of Tregs may help to assess the risk of autoimmunity/inflammation.

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Section: Discussionmentioning

confidence: 98%

Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

et al. 2017

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“…On the other hand, biochemical parameters of cirrhosis, including AST and ALT, were higher in AIH‐ and alcohol‐related cirrhosis than that of other cirrhotic groups. It has been reported that TAZ has a definite role in the regulation of the differentiation of immune cells that contribute to the progression of inflammatory and/or autoimmune diseases . The effect of the etiology of fibrosis has also been discussed in another study that investigated the role of TAZ in an experimental model, showing that TAZ induction is dependent on the severity of liver injury …”

Section: Discussionmentioning

confidence: 99%

Liver stiffness correlates with serum osteopontin and TAZ expression in human liver cirrhosis

Khajehahmadi

Mohagheghi

Nikeghbalian

et al. 2019

Annals of the New York Academy of Sciences

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The pivotal role of the extracellular matrix (ECM) as both a cause and consequence of liver fibrosis is striking. However, mechanotransducer molecules and profibrogenic factors induced by liver stiffness are still unclear. The current study aimed to investigate liver stiffness and its correlation with the expression of the transcriptional coactivator with PDZ‐binding motif (TAZ) and serum osteopontin (OPN) in human cirrhosis. In this case−control study, liver tissue stiffness was determined using atomic force microscopy in cirrhotic livers (n = 38) of different etiologies and in controls (n = 10). Immunohistochemical and qRT‐PCR analyses were performed to analyze TAZ expression. Besides, western blotting and ELISA were performed to assess liver Indian hedgehog and serum OPN levels, respectively. Liver stiffness, TAZ expression, and hepatic gene expression and serum protein levels of OPN were significantly increased in patients with cirrhosis compared with the control groups (all P < 0.001), specifically in autoimmune‐ and alcohol‐related cirrhosis. In cirrhotic patients, liver stiffness was significantly associated with the expression of nuclear TAZ and OPN. The correlation between matrix stiffness as a mechanical property, TAZ as a potential mechanotransducer, and OPN as a matricellular factor suggests possible effects of mechanical features of the ECM on the expression of the aforementioned profibrogenic markers, which is predominant in autoimmune‐ and alcohol‐related cirrhosis.

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“…While LIF showed no effect on the CD4 + T-cell proliferation (Fig 1L), LIF promoted colon epithelial cell proliferation in a dose-dependent manner ( Fig 1M). YAP expression in T cells was quite low ( Fig 1I); its paralog, transcriptional coactivator with postsynaptic density 65-disk large-zonula occludens 1-binding (PDZ) motif (TAZ), plays a pivotal role in regulating the differentiation of Treg cells and Th17 cells, but YAP is not involved in this process (Geng et al, 2017). YAP expression in T cells was quite low ( Fig 1I); its paralog, transcriptional coactivator with postsynaptic density 65-disk large-zonula occludens 1-binding (PDZ) motif (TAZ), plays a pivotal role in regulating the differentiation of Treg cells and Th17 cells, but YAP is not involved in this process (Geng et al, 2017).…”

Section: High Lif and Lifr Expression In The Inflamed Colon Differentmentioning

confidence: 99%

STAT 4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

et al. 2019

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T helper 17 (Th17)‐cell differentiation triggered by interleukin‐6 (IL‐6) via STAT3 activation promotes inflammation in inflammatory bowel disease (IBD) patients. However, leukemia inhibitory factor (LIF), an IL‐6 family cytokine, restricts inflammation by blocking Th17‐cell differentiation via an unknown mechanism. Here, we report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C‐terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis‐inducible elements (SIEs) and noncanonical “AGG” elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3‐dependent Il17a/Il17f promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, serves as a potential therapy for IBD.

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

Cited by 166 publications

References 54 publications

Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

Liver stiffness correlates with serum osteopontin and TAZ expression in human liver cirrhosis

STAT 4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

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