Themis regulates metabolic signaling and effector functions in CD4+ T cells by controlling NFAT nuclear translocation

Prasad, Mukul; Brzostek, Joanna; Gautam, Namrata; Balyan, Renu; Rybakin, Vasily; Gascoigne, Nicholas R. J.

doi:10.1038/s41423-020-00578-4

Cited by 13 publications

(13 citation statements)

References 44 publications

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“… 30 NFAT proteins also take part in metabolic signaling and effector functions. 29 NFAT5, a member of the Rel transcription factor family, is involved in the pathogenesis of diverse cancers. It was reported that NFAT5 acted as an oncogene in renal cancer, breast cancer, pancreatic cancer, and glioblastoma.…”

Section: Discussionmentioning

confidence: 99%

Circ_0001944 Contributes to Glycolysis and Tumor Growth by Upregulating NFAT5 Through Acting as a Decoy for miR-142-5p in Non-Small Cell Lung Cancer

Dou¹,

Tian²,

Wang³

et al. 2021

CMAR

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Background: Circular RNAs (circRNAs) participate in the tumorigenesis of various cancers. CircRNA hsa_circ_0001944 (circ_0001944), derived from the TCONS_l2_00030860 gene, has been uncovered to be upregulated in NSCLC (non-small cell lung cancer). Nevertheless, the influence of circ_0001944 on glycolysis and tumor growth in NSCLC is unclear. Methods: Expression trend of circ_0001944 in NSCLC tissues and cells were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Loss-of-function experiments were performed to assess the influence of circ_0001944 knockdown on proliferation, migration, invasion, and glycolysis of NSCLC cells. Protein levels were assessed by Western blotting. The regulatory mechanism of circ_0001944 was analyzed by bioinformatics analysis, dual-luciferase reporter assay, and/or RNA pull-down assay. The tumorigenicity of circ_0001944 was confirmed by xenograft assay. Results: Circ_0001944 was highly expressed in NSCLC, and NSCLC patients with high expression of circ_0001944 had a worse prognosis. Circ_0001944 silencing decreased xenograft tumor growth in vivo and repressed proliferation, migration, invasion, and glycolysis of NSCLC cells in vitro. Circ_0001944 was verified as a decoy for microRNA (miR)-142-5p, which targeted NFAT5 (nuclear factor of activated T cells 5). MiR-142-5p was downregulated while NFAT5 was upregulated in NSCLC. Both miR-142-5p inhibition and NFAT5 overexpression offset the suppressive impact of circ_0001944 silencing on proliferation, migration, invasion, and glycolysis of NSCLC cells. Circ_0001944 adsorbed miR-142-5p to elevate NFAT5 expression in NSCLC cells. Conclusion: Circ_0001944 promotes proliferation, migration, invasion, and glycolysis of NSCLC cells by upregulating NFAT5 through adsorbing miR-142-5p, offering a novel mechanism for understanding the advancement of NSCLC.

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Section: Discussionmentioning

confidence: 99%

Circ_0001944 Contributes to Glycolysis and Tumor Growth by Upregulating NFAT5 Through Acting as a Decoy for miR-142-5p in Non-Small Cell Lung Cancer

Dou¹,

Tian²,

Wang³

et al. 2021

CMAR

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“…Inhibition of mTOR by rapamycin leads to cell cycle arrest and is a potent T cell immunosuppressant [46]. The T-cell-specific protein Themis, which is important in thymocyte positive selection, has recently been shown to affect the AKT pathway and its downstream effects in mature T cells [47], and also affects metabolism [48,49].…”

Section: Metabolic Reprogramming During T Cell Activationmentioning

confidence: 99%

The Ups and Downs of Metabolism during the Lifespan of a T Cell

Balyan

Gautam

Gascoigne

2020

IJMS

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Understanding the various mechanisms that govern the development, activation, differentiation, and functions of T cells is crucial as it could provide opportunities for therapeutic interventions to disrupt immune pathogenesis. Immunometabolism is one such area that has garnered significant interest in the recent past as it has become apparent that cellular metabolism is highly dynamic and has a tremendous impact on the ability of T cells to grow, activate, and differentiate. In each phase of the lifespan of a T-cell, cellular metabolism has to be tailored to match the specific functional requirements of that phase. Resting T cells rely on energy-efficient oxidative metabolism but rapidly shift to a highly glycolytic metabolism upon activation in order to meet the bioenergetically demanding process of growth and proliferation. However, upon antigen clearance, T cells return to a more quiescent oxidative metabolism to support T cell memory generation. In addition, each helper T cell subset engages distinct metabolic pathways to support their functional needs. In this review, we provide an overview of the metabolic changes that occur during the lifespan of a T cell and discuss several important studies that provide insights into the regulation of the metabolic landscape of T cells and how they impact T cell development and function.

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“…Themis interacts with and regulates the phosphatases Shp1 ( Ptpn6 ) and Shp2 ( Ptpn11 ), although the precise mechanism is controversial ( 39 , 41 – 43 ). Themis deficiency affects the metabolic response of T cells to TCR stimulation ( 44 ). Post-selection deletion of Themis reduces the homeostatic response of peripheral CD8 + T cells to self-pMHC ( 45 ).…”

Section: Introductionmentioning

confidence: 99%

Expansion of an Unusual Virtual Memory CD8+ Subpopulation Bearing Vα3.2 TCR in Themis-Deficient Mice

et al. 2021

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Deletion of the gene for Themis affects T cell selection in the thymus, which would be expected to affect the TCR repertoire. We found an increased proportion of cells expressing Vα3.2 (TRAV9N-3) in the peripheral CD8+ T cell population in mice with germline Themis deficiency. Analysis of the TCRα repertoire indicated it was generally reduced in diversity in the absence of Themis, whereas the diversity of sequences using the TRAV9N-3 V-region element was increased. In wild type mice, Vα3.2+ cells showed higher CD5, CD6 and CD44 expression than non-Vα3-expressing cells, and this was more marked in cells from Themis-deficient mice. This suggested a virtual memory phenotype, as well as a stronger response to self-pMHC. The Vα3.2+ cells responded more strongly to IL-15, as well as showing bystander effector capability in a Listeria infection. Thus, the unusually large population of Vα3.2+ CD8+ T cells found in the periphery of Themis-deficient mice reflects not only altered thymic selection, but also allowed identification of a subset of bystander-competent cells that are also present in wild-type mice.

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Themis regulates metabolic signaling and effector functions in CD4+ T cells by controlling NFAT nuclear translocation

Cited by 13 publications

References 44 publications

Circ_0001944 Contributes to Glycolysis and Tumor Growth by Upregulating NFAT5 Through Acting as a Decoy for miR-142-5p in Non-Small Cell Lung Cancer

Circ_0001944 Contributes to Glycolysis and Tumor Growth by Upregulating NFAT5 Through Acting as a Decoy for miR-142-5p in Non-Small Cell Lung Cancer

The Ups and Downs of Metabolism during the Lifespan of a T Cell

Expansion of an Unusual Virtual Memory CD8+ Subpopulation Bearing Vα3.2 TCR in Themis-Deficient Mice

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