Partners in transcription: NFAT and AP-1

Macián, Fernando; López-Rodrı́guez, Cristina; Rao, Anjana

doi:10.1038/sj.onc.1204386

Cited by 702 publications

(593 citation statements)

References 111 publications

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“…However, induction of cytokine production is also mediated by multiple transcription factors, and we therefore studied in more detail the basis for inhibition of cytokine production in T cells with DDIT3 overexpression. We examined the effects of DDIT3 on NF-kB, NFAT, and AP-1 functions, because these are key transcription factors for production of a number of cytokines upon T cell activation (33)(34)(35). Reporter genes for which expression is promoted by NF-kB, NFAT, and AP-1 were cotransfected with a DDIT3 expression vector into Jurkat T cells, and the cells were activated by PMA/ionomycin to mimic signal transduction from TCR/costimulation.…”

Section: Alteration Of Gene Expression Is Induced By Lat Inhibitionmentioning

confidence: 99%

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

Hayashi

Jutabha

Endou³

et al. 2013

The Journal of Immunology

141

117

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Activation of T cells accompanies remarkable enhancement of metabolism. Sufficient and continuous nutrient supply is therefore important to support immune reaction in T cells. However, the mechanism of the promotion of nutrient incorporation in activated T cells has not been elucidated. In this study, we show that L-type amino acid transporter 1 (LAT1) is a major transporter for essential amino acids into activated human T cells. CD3/CD28 stimulation in primary human T cells triggered dramatic induction of LAT1 expression mediated by NF-κB and AP-1. Functional disturbance of LAT1 by a specific inhibitor and by small interfering RNA in human T cells suppressed essential amino acid uptake and induced a stress response mediated by DNA damage–inducible transcript 3 to attenuate cytokine production via inhibition of NF-κB and NFAT activities. These results uncover the previously unknown mechanism by which T cells accelerate essential amino acid uptake upon activation and adapt to essential amino acid starvation. Our results also raise the possibility for application of an LAT1 inhibitor as a new drug for therapy of disease caused by exaggerated immune response.

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Section: Alteration Of Gene Expression Is Induced By Lat Inhibitionmentioning

confidence: 99%

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

Hayashi

Jutabha

Endou³

et al. 2013

The Journal of Immunology

141

117

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“…In the nucleus, NFAT family members associate with other nuclear transcription factors (e.g. JUN, GATA4, IRF, C/EBP) depending on the cell type, to mediate transcription of specific genes including cytokine and cytokine receptor genes [15][16][17]. In addition to the regulation of their nuclear localisation by phosphorylation/dephosphorylation, NFAT members can also be regulated at the level of gene expression.…”

Section: Introductionmentioning

confidence: 99%

Nuclear factor of activated T (NFAT) cells activity within CD4+ T cells is influenced by activation status and tissue localisation

Harris¹,

Watt²,

MacLenachan³

et al. 2006

Microbes and Infection

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Nuclear factor of activated T (NFAT) cells is a family of transcription factors important for the regulation of cytokine expression by CD4+ T cells. Whilst a number of studies have examined NFAT activity of in vitro generated CD4+ T helper (Th)1 and Th2 cells, regulation of NFAT during in vivo immune responses has yet to be elucidated. We show that NFAT activity in CD4+ T cells peaked at early time-points in the draining mediastinal lymph node of mice infected with influenza A (Flu) or Nippostrongylus brasiliensis (Nb). In contrast, low NFAT transcriptional activity was detected in CD4+ T cells isolated from the lung of either Flu or Nb infected mice, despite a greater proportion of cytokine-producing cells being present at this site. These findings indicate that the activation status and tissue microenvironment of effector CD4+ T cells can determine their requirement for NFAT-mediated transcription.

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“…However, in T cells activation, CD28 co-stimulation strongly activates additional pathways, in particular the Ras/MAPK/AP-1 signaling pathway, which are otherwise poorly stimulated by TCR engagement. Following costimulation, NFAT cooperates with the AP-1 family of transcription factors, and possibly others, to induce the expression of activation-associated genes [20,21]. In contrast to normal activation, anergic conditions appear to lead to an unbalanced activation of NFAT and translocation of NFAT proteins to the nucleus in the absence of AP-1, thereby inducing the expression of anergy-associated genes [15].…”

Section: Transcriptional Regulation Of E3 Ligases In T-cell Tolerancementioning

confidence: 99%

E3 ubiquitin ligases in T‐cell tolerance

Paolino

Penninger

2009

Eur J Immunol

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The immune system uses several mechanisms of central and peripheral tolerance in order to prevent the activation of T lymphocytes toward self-antigens. Although the importance of immune self-tolerance has been established for a long time, some essential cellular and molecular mechanisms of T-cell tolerance have only been recently revealed. Once thought to be a recycling system, protein ubiquitylation by E3 ligases has now emerged as a regulated and crucial modulator of immune responses, and more importantly as a key signaling pathway involved in T-cell tolerance. In this review, we highlight our current understanding of the transcriptional and molecular signaling mechanisms involved in ubiquitylation-mediated T-cell tolerance.Key words: Autoimmunity . Cbl-b . E3 ligase . T-cell tolerance . Ubiquitylation IntroductionUpon activation, the immune system orchestrates robust and potentially destructive responses intended to eliminate the immunogenic antigen. Thus, immune system activation is under stringent control to prevent a detrimental immune response against self-antigens. The processes that ensure unresponsiveness toward self-antigens are known as immunological tolerance and, in their absence or failure, autoimmunity occurs [1]. Central tolerance mechanisms operate in the thymus to eliminate potentially self-reactive thymocytes and generate (T reg ) suppressor cells [2]. In addition, several peripheral tolerance mechanisms act to prevent self-reactivity once mature T cells have reached the periphery. These peripheral mechanisms of tolerance include the following: (i) immunological ignorance to selfantigens expressed at low levels or in immunoprivileged sites; (ii) active immunosuppression by Foxp31 T reg cells; (iii) activation-induced cell death of autoreactive T cells and (iv) induction of a state of unresponsiveness known as T-cell anergy [3].During the past few years, extensive research has revealed new insights into the cellular and molecular mechanisms necessary to induce and maintain T-cell tolerance. In particular, ubiquitylation of proteins by E3 ligases has emerged as a novel and indispensable signaling pathway that regulates T-cell tolerance toward self-antigens [4][5][6]. The ubiquitylation processUbiquitylation is an important mechanism of post-translational modification of proteins by which the 76-aa polypeptide ubiquitin, Ub, is covalently attached to a substrate protein. This process occurs in a stepwise manner, requiring the participation of three enzymes: a ubiquitin-activating enzyme E1, responsible for the first binding and activation of the Ub; a second ubiquitinconjugating enzyme E2, which receives the activated Ub from the E1; and a third ubiquitin-ligase E3 that catalyzes the final covalent transfer of the Ub from the E2 enzyme to the protein substrate [7]. Once thought to only mediate proteosomal degradation, the ubiquitylation of a protein can have multiple effects, including altered subcellular localization, regulation of protein-protein interactions, and functional modulation. The fa...

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Partners in transcription: NFAT and AP-1

Cited by 702 publications

References 111 publications

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

Nuclear factor of activated T (NFAT) cells activity within CD4+ T cells is influenced by activation status and tissue localisation

E3 ubiquitin ligases in T‐cell tolerance

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