The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation

Lü, Dan; Liu, Liang; Ji, Xin; Gao, Yanan; Chen, Xi; Liu, Yu; Liu, Yang; Zhao, Xuyang; Li, Yan; Li, Yunqiao; Jin, Yan; Zhang, Yu; McNutt, Michael A.; Yin, Yuxin

doi:10.1038/ni.3278

Cited by 122 publications

(109 citation statements)

References 46 publications

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“…Deficiency of Fam64a inhibited Th17 cell differentiation but had no obvious effects on the differentiation of Th1, Th2, or iTreg cells. Some other proteins, such as SOCS3, DUSP2, TRIM28, and PKC-θ, have also been reported to regulate Th17 cell differentiation via modulating STAT3 activity (35)(36)(37)(38). For examples, DUSP2 can mediate STAT3 dephosphorylation and suppress Th17 cell differentiation (35); TRIM28 is recruited to STAT3-occupied genes and mediates epigenetic activation during Th17 cell differentiation (36); PKC-θ can up-regulate STAT3 expression to promote Th17 cell differentiation (37).…”

Section: Discussionmentioning

confidence: 99%

FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitis-associated carcinogenesis

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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STAT3 is a transcription factor that plays central roles in various physiological processes, including differentiation of Th cells. Its deregulation results in serious diseases, including inflammatory diseases and cancer. The mechanisms related to how STAT3 activity is regulated remain enigmatic. Here we show that overexpression of FAM64A potentiates IL-6-induced activation of STAT3 and expression of downstream target genes, whereas deficiency of FAM64A has the opposite effects. FAM64A interacts with STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes. Deficiency of Fam64a significantly impairs differentiation of Th17 but not Th1 or induced regulatory T cells (iTreg). In addition, Fam64a deficiency attenuates experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, which is correlated with decreased differentiation of Th17 cells and production of proinflammatory cytokines. Furthermore, Fam64a deficiency suppresses azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) in mice. These findings suggest that FAM64A regulates Th17 differentiation and colitis and inflammation-associated cancer by modulating transcriptional activity of STAT3.

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Section: Discussionmentioning

confidence: 99%

FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitis-associated carcinogenesis

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Also, a role for JKAP is identified in the inhibition of IL-6-induced STAT3 activation by estradiol (34). And another member of DUSPs, DUSP2, is also down-regulated in IBD patients, and moderate association of with JKAP is discovered (35). The phosphatase DUSP2 also regulates Th17 differentiation by controlling the activity of the transcription activator STAT.…”

Section: Discussionmentioning

confidence: 99%

JNK Pathway-Associated Phosphatase/DUSP22 Suppresses CD4+ T-Cell Activation and Th1/Th17-Cell Differentiation and Negatively Correlates with Clinical Activity in Inflammatory Bowel Disease

et al. 2017

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This study aimed to investigate the role of JNK pathway-associated phosphatase (JKAP) in inflammatory bowel disease (IBD). JKAP expression was analyzed in the intestinal mucosa of 81 IBD patients and 25 healthy controls (HCs) by qPCR and immunoblotting. The correlations of JKAP with clinical activity and inflammatory cytokines were performed. JKAP expression before and after infliximab treatment was also measured. CD4+ T cells were isolated from peripheral blood in active IBD patient and HCs and transduced with lentivirus-encoding JKAP (LV-JKAP), anti-JKAP (LV-anti-JKAP), or empty vector (LV-scramble), and JKAP functions on IBD CD4+ T cells were subsequently investigated. JKAP expression was decreased in inflamed mucosa of active IBD patients and was negatively correlated with disease activity [Crohn’s disease activity index (CDAI), Mayo index, C-reactive protein, and erythrocyte sedimentation rate], interleukin-17, and tumor necrosis factor (TNF)-α levels. Anti-TNF-α treatment up-regulated JKAP expression in CD patients, and baseline JKAP expression was elevated in response patients than in failure patients. Transduction of LV-JKAP into CD4+ T cells inhibited the percentages of CD25+ and CD69+ cells and proliferation. Moreover, inhibition of JKAP promotes Th1/Th17 cell differentiation. Our data indicated that the decreased expression of JKAP in intestinal mucosa contributed to the pathogenesis of IBD, through facilitating CD4+ T-cell activation, proliferation, and Th1/Th17-cell differentiation.

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“…Since IL-2 is a factor critically required for induction of Tregs and at the same time can prevent Th17 differentiation [52, 53], it is tempting to speculate that Y. pseudotuberculosis mediated alterations in IL-2 production also contribute to the skewing from Tregs to Th17 cells, and the lower frequency of de novo-induced Tregs might enable enhanced generation of Th17 cells. Yet, whether YopH is the master regulator of Y. pseudotuberculosis -mediated modulation of T cell differentiation or other mechanisms contribute to the fine-tuning of the closely related transcriptional regulation of Tregs and Th17 cells [54, 55] remains to be elucidated. In this context, it will be also interesting to dissect why modulation of naïve CD4 + T cells with Yptb-WT-Bla did only affect expression of the cytokine IL-17 in Th17-polarizing cultures, but not the expression of the Th17 lineage specification factor RORγt, although under Treg-inducing conditions a severe impact on the expression of the Treg lineage specification factor Foxp3 could be observed.…”

Section: Discussionmentioning

confidence: 99%

Yersinia pseudotuberculosis supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling

Pásztói

Bonifacius

Pezoldt

et al. 2017

Cell. Mol. Life Sci.

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Adaptive immunity critically contributes to control acute infection with enteropathogenic Yersinia pseudotuberculosis; however, the role of CD4+ T cell subsets in establishing infection and allowing pathogen persistence remains elusive. Here, we assessed the modulatory capacity of Y. pseudotuberculosis on CD4+ T cell differentiation. Using in vivo assays, we report that infection with Y. pseudotuberculosis resulted in enhanced priming of IL-17-producing T cells (Th17 cells), whereas induction of Foxp3+ regulatory T cells (Tregs) was severely disrupted in gut-draining mesenteric lymph nodes (mLNs), in line with altered frequencies of tolerogenic and proinflammatory dendritic cell (DC) subsets within mLNs. Additionally, by using a DC-free in vitro system, we could demonstrate that Y. pseudotuberculosis can directly modulate T cell receptor (TCR) downstream signaling within naïve CD4+ T cells and Tregs via injection of effector molecules through the type III secretion system, thereby affecting their functional properties. Importantly, modulation of naïve CD4+ T cells by Y. pseudotuberculosis resulted in an enhanced Th17 differentiation and decreased induction of Foxp3+ Tregs in vitro. These findings shed light to the adjustment of the Th17-Treg axis in response to acute Y. pseudotuberculosis infection and highlight the direct modulation of CD4+ T cell subsets by altering their TCR downstream signaling.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-017-2516-y) contains supplementary material, which is available to authorized users.

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The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation

Cited by 122 publications

References 46 publications

FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitis-associated carcinogenesis

FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitis-associated carcinogenesis

JNK Pathway-Associated Phosphatase/DUSP22 Suppresses CD4+ T-Cell Activation and Th1/Th17-Cell Differentiation and Negatively Correlates with Clinical Activity in Inflammatory Bowel Disease

Yersinia pseudotuberculosis supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling

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