LFA-1-Dependent HuR Nuclear Export and Cytokine mRNA Stabilization in T Cell Activation

Wang, Jin Gene; Collinge, Mark; Ramgolam, Vinod S.; Ayalon, Oran; Fan, Xinhao; Pardi, Ruggero; Bender, Jeffrey R.

doi:10.4049/jimmunol.176.4.2105

Cited by 76 publications

(87 citation statements)

References 56 publications

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“…Possible explanations for the simultaneous presence of transcribed mRNA without surface molecule expression (51, 52) may involve mRNA stabilization (52) or regulation of ribosomal entry (53) by as yet undescribed factors.…”

Section: Discussionmentioning

confidence: 99%

Differential NKp30 Inducibility in Chimpanzee NK Cells and Conserved NK Cell Phenotype and Function in Long-Term HIV-1-Infected Animals

Rutjens

Mazza

Biassoni

et al. 2007

The Journal of Immunology

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HIV-1 infection in chimpanzees, the closest human relative, rarely leads to disease progression. NK cells contribute to the shaping of adaptive immune responses in humans and show perturbed phenotype and function during HIV-1 infection. In this study, we provide full phenotypic, molecular, and functional characterization for triggering molecules (NKp46, NKp30 NKp80, and NKG2D) on Pan troglodytes NK cells. We demonstrate that, in this AIDS-resistant species, relevant differences to human NK cells involve NKp80 and particularly NKp30, which is primarily involved in NK-dendritic cell interactions. Resting peripheral chimpanzee NK cells have low or absent NKp30 molecule expression due to posttranscriptional regulation and increase its levels upon in vitro activation. Following long-standing HIV-1 infection, peripheral NK cells in chimpanzees have conserved triggering receptor expression and display moderate phenotypic and functional decreases only once activated and cultured in vitro. These data suggest that one of the keys to successful lentivirus control may reside in part in a different regulation of NK cell-triggering receptor expression.

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Section: Discussionmentioning

confidence: 99%

Differential NKp30 Inducibility in Chimpanzee NK Cells and Conserved NK Cell Phenotype and Function in Long-Term HIV-1-Infected Animals

Rutjens

Mazza

Biassoni

et al. 2007

The Journal of Immunology

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“…In Jurkat cells, PKC phosphorylates the RNA-binding protein NF-90, which allows NF-90 to bind and stabilize Il2 mRNA (15). Similarly, HuR can stabilize Ifng mRNA (38), and in vitro data show that PKC can phosphorylate HuR (39). Thus, it is tempting to speculate that HuR and NF-90 promote Ifng and Il2 mRNA stability in primary CD8 + T cells in a PKC-mediated manner.…”

Section: Pkc-signaling Stabilizes Ifng and Il2 Transcripts For Optimamentioning

confidence: 96%

Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8⁺T cells

Salerno

Paolini

Stark

et al. 2017

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

127

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Effective T cell responses against invading pathogens require the concerted production of three key cytokines: TNF-α, IFN-γ, and IL-2. The cytokines functionally synergize, but their production kinetics widely differ. How the differential timing of expression is regulated remains, however, poorly understood. We compared the relative contribution of transcription, mRNA stability, and translation efficiency on cytokine production in murine effector and memory CD8 + T cells. We show that the immediate and ample production of TNF-α is primarily mediated by translation of preformed mRNA through protein kinase C (PKC)-induced recruitment of mRNA to polyribosomes. Also, the initial production of IFN-γ uses translation of preformed mRNA. However, the magnitude and subsequent expression of IFN-γ, and of IL-2, depends on calcium-induced de novo transcription and PKC-dependent mRNA stabilization. In conclusion, PKC signaling modulates translation efficiency and mRNA stability in a transcript-specific manner. These cytokine-specific regulatory mechanisms guarantee that T cells produce ample amounts of cytokines shortly upon activation and for a limited time.T cells | cytokine production | PKC | mRNA stability | translation efficiency

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“…has been shown for cytokines interleukin-2 and TNF␣ mRNA (27,28). ASF/SF2 is known to regulate RNA stability of the PKCI-1-related mRNA (29) and is also involved in translation (30), and it is not known whether ASF/SF2 may also regulate stability and translation of CD3.…”

Section: Discussionmentioning

confidence: 99%

Alternative Splicing Factor/Splicing Factor 2 Regulates the Expression of the ζ Subunit of the Human T Cell Receptor-associated CD3 Complex

Moulton

Tsokos

2010

Journal of Biological Chemistry

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T cells from patients with systemic lupus erythematosus express decreased levels of the T cell receptor-associated CD3 chain, a feature directly linked to their aberrant function. The decrease in CD3 protein expression is in part due to decreased levels of functional wild type isoform of the 3-untranslated region (UTR) of CD3 mRNA with concomitant increased levels of an unstable alternatively spliced isoform. In order to identify factors involved in the post-transcriptional regulation of CD3, we performed mass spectrometric analysis of Jurkat T cell nuclear proteins "pulled down" by a CD3 3-UTR oligonucleotide, which identified the splicing protein alternative splicing factor/splicing factor 2 (ASF/SF2). We show for the first time that ASF/SF2 binds specifically to the 3-UTR of CD3 and regulates expression of CD3 protein by limiting the production of the alternatively spliced isoform. During activation of human T cells, an increase in the wild type CD3 mRNA is associated with increased expression of ASF/SF2. Finally, we show a significant correlation between ASF/SF2 and CD3 protein levels in T cells from systemic lupus erythematosus patients. Thus, our results identify ASF/SF2 as a novel factor in the regulation of alternative splicing of the 3-UTR of CD3 and protein expression in human T cells. Systemic lupus erythematosus (SLE)2 is a chronic multisystem autoimmune disease characterized by abnormal cellular and humoral immune responses and a disease course marked by relapses (flares) and remissions. A key signaling defect of T cells in SLE patients is their aberrant expression of the T cell receptor (TCR)-associated CD3 chain, the crucial signaling transducer of the TCR (1). CD3 protein expression is heterogeneous in SLE patients and tends to inversely correlate with severity of the disease. Consequently, many patients exhibit decreased (20 -80% of normal) levels of CD3 protein, whereas others express normal levels of CD3 protein when compared with healthy individuals. The homologous Fc receptor ␥ chain replaces CD3 chain in the TCR CD3 complex in these CD3-low T cells (2) and recruits the spleen tyrosine kinase (Syk) instead of the normally recruited -associated protein (ZAP-70) (3). This "rewiring" of the TCR, along with preclustered TCRbearing lipid rafts, leads to aberrantly increased phosphorylation and calcium flux upon activation (4). Despite this overexcitable phenotype, SLE T cells fail to produce the vital cytokine interleukin-2. Replenishment of the CD3 in the SLE T cells in vitro reverts this phenotype and more importantly restores interleukin-2 production (5). Although these findings highlight a central role for the aberrant CD3 expression in the SLE T cell defect, the mechanisms regulating the expression of CD3 chain in physiology and in disease are not fully understood.The CD3 gene spans 31 kb in the chromosome 1q23.1 locus, a region associated with SLE susceptibility (6), and bears eight exons separated by introns ranging from 700 bp to greater than 8 kb (Fig. 1A, top) (7,8). The CD3 mRNA is a 1...

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LFA-1-Dependent HuR Nuclear Export and Cytokine mRNA Stabilization in T Cell Activation

Cited by 76 publications

References 56 publications

Differential NKp30 Inducibility in Chimpanzee NK Cells and Conserved NK Cell Phenotype and Function in Long-Term HIV-1-Infected Animals

Differential NKp30 Inducibility in Chimpanzee NK Cells and Conserved NK Cell Phenotype and Function in Long-Term HIV-1-Infected Animals

Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8⁺T cells

Alternative Splicing Factor/Splicing Factor 2 Regulates the Expression of the ζ Subunit of the Human T Cell Receptor-associated CD3 Complex

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LFA-1-Dependent HuR Nuclear Export and Cytokine mRNA Stabilization in T Cell Activation

Cited by 76 publications

References 56 publications

Differential NKp30 Inducibility in Chimpanzee NK Cells and Conserved NK Cell Phenotype and Function in Long-Term HIV-1-Infected Animals

Differential NKp30 Inducibility in Chimpanzee NK Cells and Conserved NK Cell Phenotype and Function in Long-Term HIV-1-Infected Animals

Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8+T cells

Alternative Splicing Factor/Splicing Factor 2 Regulates the Expression of the ζ Subunit of the Human T Cell Receptor-associated CD3 Complex

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Distinct PKC-mediated posttranscriptional events set cytokine production kinetics in CD8⁺T cells