NFAT5 or TonEBP or OREBP

INTRODUCTION: The blockade of interleukine-1 (anakinra and canakinumab) is a well-known highly effective tool for monogenic autoinflammatory diseases (AIDs), such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, hyperimmunoglobulinaemia D syndrome, and cryopyrin-associated periodic syndrome, but this treatment has not been assessed for patients with undifferentiated AIDs (uAIDs). Our study aimed to assess the safety and efficacy of canakinumab for patients with uAIDs...

Age-related microglial activation is associated with cognitive impairment. Tonicity-responsive enhancer-binding protein (TonEBP) is a critical mediator of microglial activation in response to neuroinflammation. However, the precise role of TonEBP in the middle-aged brain is not yet known. We used TonEBP haploinsufficient mice to investigate the role of TonEBP in middle-aged or amyloid β oligomer (AβO)-injected brains and examined the effect of TonEBP knockdown on AβO-treated BV2 microglial cells...

The bone-derived hormone fibroblast growth factor-23 (FGF23) has recently received much attention due to its association with chronic kidney disease and cardiovascular disease progression. Extracellular sodium concentration ([Na+ ]) plays a significant role in bone metabolism. Hyponatremia (lower serum [Na+ ]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+ ] on FGF23 production...

Chronic lymphocytic leukemia (CLL) mainly affects the health of older adults and is difficult to cure. Upstream stimulatory factor 2 (USF2) has been implicated in several diseases and conditions including cancers. However, the effect of USF2 on CLL has not been elucidated. To investigate the effect of USP2 on proliferation and autophagy of CLL, and to explore the underlying mechanism. The mRNA of USF2 and STIP1 homology and U-Box containing protein 1 (STUB1) was analyzed using qRT-PCR. Western blots were used to evaluate the expression level of USF2, LC3II, Beclin-1, P62, STUB1, and NFAT5...

Homeostatic control of intracellular ionic strength is essential for protein, organelle and genome function, yet mechanisms that sense and enable adaptation to ionic stress remain poorly understood in animals. We find that the transcription factor NFAT5 directly senses solution ionic strength using a C-terminal intrinsically disordered region. Both in intact cells and in a purified system, NFAT5 forms dynamic, reversible biomolecular condensates in response to increasing ionic strength. This self-associative property, conserved from insects to mammals, allows NFAT5 to accumulate in the nucleus and activate genes that restore cellular ion content...

[This retracts the article DOI: 10.1155/2022/6481846.].

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by joint pain and swelling, synovial hyperplasia, cartilage damage, and bone destruction. The mechanisms of dendritic cell (DC) and T cell-mediated crosstalk have gradually become a focus of attention. DCs regulate the proliferation and differentiation of CD4+ T cell subtypes through different cytokines, surface molecules, and antigen presentation. DC-T cell crosstalk also blocks antigen presentation by DCs, ultimately maintaining immune tolerance...

Long non-coding RNAs (lncRNAs) interaction with RNA-Binding proteins (RBPs) plays an important role in immunological processes. The generation of antigen-specific Th17 cells is closely associated with autoimmune pathogenesis. However, the function of lncRNA-RBP interactions in the regulation of pathogenic Th17 cell responses during autoimmunity remains poorly understood. Here, we found that lncRNA Neat1, highly expressed in Th17 cells, promoted antigen-specific Th17 cell responses. Both global and CD4+ T cell-specific knockdown of Neat1 protected mice against the development of experimental autoimmune uveitis (EAU)...

Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. Here we found that NFAT5, an NFAT family transcription factor that lacks an AP-1 docking site, was highly expressed in exhausted CD8+ T cells in the context of chronic infections and tumors but was selectively required in tumor-induced CD8+ T cell exhaustion...

Hyperosmotic stress occurs in several diseases, but its long-term effects are largely unknown. We used sorbitol-treated human fibroblasts in 3D culture to study the consequences of hyperosmotic stress in the skin. Sorbitol regulated many genes, which help cells cope with the stress condition. The most robustly regulated gene encodes serine protease 35 (PRSS35). Its regulation by hyperosmotic stress was dependent on the kinases p38 and JNK and the transcription factors NFAT5 and ATF2. We identified different collagens and collagen-associated proteins as putative PRSS35 binding partners...

PURPOSE: Recent studies, conducted mainly on the rodent model, have demonstrated that regulatory pathway in the skin provided by glycosaminoglycans, nuclear factor of activated T cells 5 (NFAT5), vascular endothelial growth factor C (VEGF-C) and process of lymphangiogenesis may play an important role in extrarenal regulation of sodium (Na+ ) balance, body water volume, and blood pressure. We aimed to investigate the concentrations and relations among the main factors of this pathway in human skin to confirm that this regulatory axis also exists in humans...

CD4+ T cells play a central role in the adaptive immune response through their capacity to activate, support and control other immune cells. Although these cells have become the focus of intense research, a comprehensive understanding of the underlying regulatory networks that orchestrate CD4+ T cell function and activation is still incomplete. Here, we analyzed a large transcriptomic dataset consisting of 48 different human CD4+ T cell conditions. By performing reverse network engineering, we identified six common denominators of CD4+ T cell functionality (CREB1, E2F3, AHR, STAT1, NFAT5 and NFATC3)...

Dry eye inflammation is a key step in a vicious circle and needs to be better understood in order to break it. The goals of this work were to, first, characterize alarmins and cytokines released by ocular surface cells in the hyperosmolar context and, second, study the role of NFAT5 in this process. Finally, we studied the potential action of these alarmins in ocular surface epithelial cells and macrophages via RAGE pathways. HCE and WKD cell lines were cultured in a NaCl-hyperosmolar medium and the expression of alarmins (S100A4, S100A8, S100A9, and HMGB1), cytokines (IL6, IL8, TNFα, and MCP1), and NFAT5 were assessed using RT-qPCR, ELISA and multiplex, Western blot, immunofluorescence, and luciferase assays...

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the most prevalent and severe malignant tumors in the world and its molecular mechanism is still unclear. In recent years, increasing evidence indicates the significant roles of circRNAs in NSCLC. It has been determined that 2-methoxyestradiol (2-MeOE2) exerts antitumor roles in many cancers. However, the molecular mechanism of 2-MeOE2 in regulating the development of lung cancer needs further elucidation. METHODS: The expression levels of circ_0010235, microRNA-34a-5p (miR-34a-5p), and nuclear factor of activated T cells 5 (NFAT5) were detected by quantitative real-time polymerase chain reaction (qRT-PCR)...

Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation...

OBJECTIVE: Colorectal cancer (CRC) is a prevalent gastrointestinal tumor globally. Circular RNAs (circRNAs) have been identified as regulatory players in the pathogenesis of CRC. However, it is unclear whether hsa_circ_0050102 (circPGPEP1) affects the malignant progression and immune escape in CRC. METHODS: Bioinformatics analysis and circRNA in vivo precipitation experiments were performed to analyze and identify circRNAs that mediate immune escape in CRC. Using luciferase reporter assay, RIP, RNA pull-down assay, and FISH, the interaction between circPGPEP1, miR-515-5p, and nuclear factor of activated T-cell 5 (NFAT5) was identified...

N6 -methyladenosine (m6 A) RNA methylation and its associated methyltransferase like 3 (METTL3) are involved in the development and maintenance of various tumors. The present study aimed to evaluate the cross-talk of METTL3 with glucose metabolism and reveal a novel mechanism for intrahepatic cholangiocarcinoma (ICC) progression. Real-time quantitative PCR, western blotting, and immunohistochemistry analyses suggested that METTL3 was highly expressed in ICC, which was correlated with poor patient prognosis...

Transforming growth factor-β (TGF-β) signaling is a critical driver of epithelial-to-mesenchymal transition (EMT) and cancer progression. In SMAD-dependent TGF-β signaling, activation of the TGF-β receptor complex stimulates the phosphorylation of the intracellular receptor-associated SMADs (SMAD2 and SMAD3), which translocate to the nucleus to promote target gene expression. SMAD7 inhibits signaling through the pathway by promoting the polyubiquitination of the TGF-β type I receptor (TβRI)...

Novel molecular targets for cervical cancer must be identified. This study examined the role of SLC5A3, a myo-inositol transporter, in the pathogenesis of cervical cancer. Through boinformatics analysis, we showed that the SLC5A3 mRNA levels were upregulated in cervical cancer tissues. The upregulated SLC5A3 mRNA levels were negatively correlated with survival and progression-free interval. Genes co-expressed with SLC5A3 were enriched in multiple signaling cascades involved in cancer progression. In primary/established cervical cancer cells, SLC5A3 shRNA/knockout (KO) exerted growth-inhibitory effects and promoted cell death/apoptosis...

Hepatitis B virus (HBV) infection is a global health problem and lacks effective therapies in clinic. This study attempted to investigate the role of histone deacetylase 3 (HDAC3) in HBV replication. Cells were treated with 1.3 folds of HBV genome. The expression patterns of HDAC3, miR-29a-3p, and nuclear factor of activated T-cells 5 (NFAT5) in cells were determined by real-time quantitative polymerase chain reaction and Western blot analysis. HBV replication was assessed by measurements of HBV DNA, HBV RNA, hepatitis B surface antigen, and hepatitis B E antigen...