Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

Collins, Sam; Lutz, Michael A.; Zarek, Paul E.; Anders, Robert A.; Kersh, Gilbert J.; Powell, Jonathan D.

doi:10.1002/eji.200737157

Cited by 98 publications

(117 citation statements)

References 32 publications

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“…11 Functional divergence is also evident in immune regulation: Egr-2 appears to be required for immune tolerance, whereas Egr-1 enhances T-cell activity in response to T-cell receptor engagement. 12,13 These and similar observations underline the significant differences that exist between these two structurally related members of the Egr transcription factor family.…”

supporting

confidence: 57%

“…43 Because Egr-1 and Egr-2 appear to bind to identical GC-rich DNA elements, the distinct or even opposing biological activities of Egr-1 and Egr-2 are thought to reflect the different repertoires of cofactors recruited into the transcriptional complex as the result of divergent non-DNA-binding domains. 12,44 The functional distinction between Egr-1 and Egr-2 is highlighted by genetic targeting studies demonstrating that, although Egr-1-null mice show little spontaneous phenotype, 10 loss of Egr-2 is associated with embryonic lethality. 11 Moreover, biological responses can even be antagonistically regulated by Egr-1 and Egr-2.…”

Section: Discussionmentioning

confidence: 99%

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The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

Fang

Ooka

Bhattachyya

et al. 2011

The American Journal of Pathology

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Although the early growth response-2 (Egr-2, alias Krox20) protein shows structural and functional similarities to Egr-1, these two related early-immediate transcription factors are nonredundant. Egr-2 plays essential roles in peripheral nerve myelination, adipogenesis, and immune tolerance; however, its regulation and role in tissue repair and fibrosis remain poorly understood. We show herein that transforming growth factor (TGF)-␤ induced a Smad3-dependent sustained stimulation of Egr2 gene expression in normal fibroblasts. Overexpression of Egr-2 was sufficient to stimulate collagen gene expression and myofibroblast differentiation, whereas these profibrotic TGF-␤ responses were attenuated in Egr-2-depleted fibroblasts. Genomewide transcriptional profiling revealed that multiple genes associated with tissue remodeling and wound healing were up-regulated by Egr-2, but the Egr-2-regulated gene expression profile overlapped only partially with the Egr-1-regulated gene profile. Levels of Egr-2 were elevated in lesional tissue from mice with bleomycin-induced scleroderma. Moreover, elevated Egr-2 was noted in biopsy specimens of skin and lung from patients with systemic sclerosis.These results provide the first evidence that Egr-2 is a functionally distinct transcription factor that is both necessary and sufficient for TGF-␤-induced profibrotic responses and is aberrantly expressed in lesional tissue in systemic sclerosis and in a murine model of scleroderma. Together, these findings suggest that Egr-2 plays an important nonredundant role in the pathogenesis of fibrosis. Targeting Egr-2 might represent a novel therapeutic strategy to control fibrosis.

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supporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

Fang

Ooka

Bhattachyya

et al. 2011

The American Journal of Pathology

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“…cDNA was amplified using gene-specific primers for IL-6, TNF-a [45], IL-12p19 [46], EGR-1,-2,-3 [47], IL-2 (5 0 -CAAGCAGGCCACA-GAATTGA and 5 0 -CCGCAGAGGTCCAAGTTCA), COX-2 (5 0 -TGA GTACCGCAAACGCTTCTC and 5 0 -TTTCTTTCTCTCCTGTAAGTTC TTCAA) and hypoxanthine-guanine phosphoribosyl transferase (5 0 -GCAGTACAGCCCCAAAAT and 5 0 -AACAAAGTCTGGCCTG-TATCCAA). Reactions were set up using a iQ SYBR Green Supermix (Bio-Rad, Hercules, CA).…”

Section: Real-time Pcr (Rt-pcr)mentioning

confidence: 99%

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

et al. 2009

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DC recognize microbial components through an array of receptors known as PRR. PRR initiate intracellular signals, which engender DC with the capacity to stimulate T-cell responses. Dectin-1 is a PRR that recognizes b-glucan, a major constituent of many fungi's outer cell wall. Here we show that Dectin-1 activates DC through phospholipase (PLC)c2 signaling. PLCc2-deficient DC were unable to expand antigen-specific T cells and induce T H 1 and T H 17 differentiation in response to b-glucan. Mechanistically, PLCc2-deficiency impaired the capacity of DC to secrete polarizing cytokines following exposure to b-glucan. Dectin-1 required PLCc2 to activate MAPK, AP-1 and NF-jB, which induce cytokine gene expression. Moreover, PLCc2 controlled Dectin-1-mediated NFAT activation and induction of NFAT-dependent genes such as IL-2, cyclooxigenase-2 and Egr transcription factors. We conclude that PLCc2 is a crucial signaling mediator that modifies DC gene expression program to activate DC responses to b-glucan-containing pathogens.Key words: DC . Dectin-1 . PLCg . Signaling Supporting Information available online Introduction DC play a key role in gathering information from the surrounding environment and initiating appropriate immune responses when needed [1,2]. Because they bridge innate and adaptive immunity, DC are equipped with a multitude of intracellular and cell surface receptors that sense microbial components and trigger host responses to invading pathogens. These receptors, collectively known as PRR, include TLR [3], C-type lectins such as Dectin-1 [4], scavenger receptors [5], the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the NOD-like receptors and the RIG-like receptors [6].Dectin-1 recognizes b-glucan, a major constituent of many fungi's outer cell wall [4,7] and triggers intracellular signals through a cytoplasmic tyrosine motif resembling the ITAM. Upon ligand binding, this motif is phosphorylated by src family kinases [8] and recruits the tyrosine kinase Syk [9], which initiates a signaling cascade leading to NF-kB [10], NFAT [11] and MAPK [12] activation. Along with Bcl-10 and MALT1, CARD9 is a crucial mediator in the ITAM-signaling pathway that links recognition of b-glucan by Dectin-1 to NF-kB and MAPK activation [13,14]. Overall, the Syk-CARD9 pathway is essential for [20,21]. Syk, together with the tyrosine kinases BTK and Src, activate PLCg through tyrosine phosphorylation [22]. Another downstream ITAM mediator, PI-3K, activates PLCg by generating phosphatidylinositol 3,4,5 trisphosphate, which binds the pleckstrin homology domain of PLCg, promoting PLCg recruitment to the cell membrane. Thus, the ability of Dectin-1 to initiate an ITAM-Syk-signaling pathway [9] provides a rationale for studying the role of PLCg in Dectin-1-mediated antimicrobial responses in DC.PLCg includes two isoforms, PLCg1 and PLCg2, which hydrolyze membrane phosphatidylinositol 4,5-biphosphate into inositol 1,4,5-trisphosphate and diacylglicerol (DAG) [20]. Inositol 1,4,5-trisphosphate triggers the ...

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“…Overexpression of Erg2 or Erg3 in T cells leads to higher Cbl-b expression levels, whereas Erg3 À/À T cells treated with ionomycin (a calcium ionophore used to induce anergy) are unable to upregulate . However, it is still not clear if Erg2 and Erg3 bind directly to the Cbl-b promoter or if other transcription factors are involved, including NFAT itself [28,29]. The transcription factor Foxp3 has also been reported to transcriptionally regulate the expression of Erg3 and Cbl-b, but the mechanism is not yet known [30].…”

Section: Transcriptional Regulation Of E3 Ligasesmentioning

confidence: 99%

“…Cbl-b gene expression is reported to be dependent on the early growth transcription factors Erg2 and Erg3, which are themselves induced under anergic conditions in an NFATdependent manner [15,28,29]. Erg3 À/À T cells are resistant to anergy induction and Erg3-deficient mice have increased susceptibility to autoimmunity, phenocopying Cbl-b-deficient T cells in vitro and the phenotype of Cbl-b mutant mice in vivo, respectively [28,29]. Overexpression of Erg2 or Erg3 in T cells leads to higher Cbl-b expression levels, whereas Erg3 À/À T cells treated with ionomycin (a calcium ionophore used to induce anergy) are unable to upregulate Cbl-b [29].…”

Section: Transcriptional Regulation Of E3 Ligasesmentioning

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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Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

Cited by 98 publications

References 32 publications

The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

E3 ubiquitin ligases in T‐cell tolerance

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Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

Cited by 98 publications

References 32 publications

The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

The Early Growth Response Gene Egr2 (Alias Krox20) Is a Novel Transcriptional Target of Transforming Growth Factor-β that Is Up-Regulated in Systemic Sclerosis and Mediates Profibrotic Responses

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization

E3 ubiquitin ligases in T‐cell tolerance

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Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization