Transcription factors TFE3 and TFEB are critical for CD40 ligand expression and thymus-dependent humoral immunity

Huan, Chongmin; Kelly, Matthew L.; Steele, Ryan; Shapira, Iuliana; Gottesman, Susan; Roman, Christopher

doi:10.1038/ni1378

Cited by 78 publications

(66 citation statements)

References 55 publications

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“…We and others have previously described and characterized the CD154 transcriptional promoter. 2,4,13,[18][19][20][21][22][23] In addition, we have identified a 3 0 CD154 transcriptional enhancer 5 located just downstream of the 3 0 UTR mRNA stability element. 24,25 In vitro, both the hCD154 transcriptional promoter and 3 0 enhancer element are relatively weak, despite the abundant and rapid generation of CD154 mRNA following CD4 T-cell activation.…”

Section: Discussionmentioning

confidence: 99%

“…Roman and colleagues have also recently shown that this region is rich in binding sites for TFE3 and TFEB transcription factors. 19 This novel 5 0 CD154 transcriptional enhancer, much like the IL-4 3 0 enhancer, 10 possesses multiple binding sites for NFAT and GATA proteins. In peripheral T cells the only GATA protein present is GATA-3, 27 and sitedirected disruption of individual GATA-3 sites within the context of reporter genes have minimal to moderate (B50% reduction) inhibitory effects on transcriptional enhancement perhaps because of the redundancy of binding sites in this region (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

Brunner

Genin

et al. 2008

Genes Immun

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CD154 (CD40-ligand) is a critical immune regulator. CD154 expression is tightly regulated and largely restricted to activated CD4 T cells. Using DNase I hypersensitivity site (HSS) mapping, we identified two novel HSS mapping to the human CD154 promoter element and just upstream. Both HSS were activation independent and CD4 T-cell specific. Approximately 350 bp of DNA sequence flanking the upstream HSS site was highly conserved between mouse and man, and was rich in binding sites for GATA and NFAT proteins. Gel shift and chromatin immunoprecipitation assays demonstrated both NFAT1 and the Th2 factor, GATA-3, bound this enhancer element in vitro and in vivo, respectively. A PstI/XbaI 345 bp fragment of this region acted as a transcriptional enhancer of the CD154 promoter in primary human CD4 T cells. Overexpression of repressor of GATA and a dominant negative GATA-3 protein independently inhibited transcription, whereas overexpression of wild-type GATA-3 enhanced transcriptional activity, by this element in primary CD4 T cells. Moreover, more interleukin-4-producing CD4 T cells expressed CD154 following activation than interferon-g-producing CD4 T cells. Thus, we identified a novel T-cell-specific, GATA-3 responsive, CD154 transcriptional enhancer, which may contribute to increased propensity of Th2 cells to express CD154.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

Brunner

Genin

et al. 2008

Genes Immun

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“…Reduction of Toll-like receptor 4 (TLR4) on SMS1/SMS2 knockdown macrophages after LPS stimulation. Cell surface receptors were detected as described previously (23). Briefly, control siRNA-or SMS1/2 siRNA-treated macrophages were stimulated by LPS (100 ng/ml) for 2 min and then stained with 1 mg/ml TLR4/MD-2 complex antibody (CSA-805FIJ, Stressgen) for 1 h on ice, then washed with ice-cold PBS three times before analysis on a FACScan with CellQuest software.…”

Section: Discussionmentioning

confidence: 99%

“…Cell surface receptors were detected as described previously (23). Briefly, macrophages were stimulated by LPS (100 ng/ml) for 2 min and then stained with 1 mg/ml Toll-like receptor 4 (TLR4)/MD-2 complex antibody (CSA-805FIJ; Stressgen) for 1 h on ice, then washed with ice-cold PBS three times before analysis on a FACScan with CellQuest software (Benton Dickinson).…”

Section: Toll-like Receptor 4 Analyses By Fluorescence-activated Cellmentioning

confidence: 99%

SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis

Ding

Hailemariam

et al. 2008

Journal of Lipid Research

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Sphingomyelin synthase (SMS), the last enzyme in the sphingomyelin (SM) biosynthetic pathway, uses ceramide and phosphatidylcholine as substrates to produce SM and diacylglycerol (DAG). To evaluate the role of SMS in apoptosis, we generated Chinese hamster ovary cells that stably express human SMS1 or SMS2. We found that SMS1 or SMS2 overexpression results in a significant increase in cellular levels of SM (24% or 20%) and DAG (35% or 31%), respectively, compared with controls. Cells overexpressing SMS1 or SMS2 were more likely to undergo lysis mediated by lysenin (a protein that causes lysis through its affinity with SM-rich microdomains in the plasma membrane) than were controls, indicating SM enrichment of the plasma membrane. SMS1 and SMS2 overexpression also led to higher retention of DiIC16 fluorescence compared with wild-type cells, indicating an increased number of detergentinsoluble microdomains and significantly increased tumor necrosis factor-a-mediated apoptosis. To further evaluate the relationship between SMS activity and cell apoptosis, we used SMS1 and SMS2 small interfering RNA (siRNA) to knock down their mRNA in THP-1-derived macrophages. We found that SMS1 or SMS2 siRNA significantly reduces intracellular SM (by 20% or 23%), plasma membrane SM (as indicated by the rate of lysenin-mediated cell lysis), and DAG levels (24% or 20%), respectively, while significantly reducing lipopolysaccharide-mediated apoptosis compared with controls. These results indicate that SMS1 and SMS2 are key factors in the control of SM and DAG levels within the cell and thus influence apoptosis.-Ding, T., Z. Li, T. Hailemariam, S. Mukherjee, F. R. Maxfield, M-P. Wu, and X-C. Jiang. SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis. J. Lipid Res. 2008. 49: 376-385.

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“…In addition, combined depletion of TFEB and TFE3 in T cells leads to a defective T-celldependent antibody response (Huan et al, 2006), whereas TFEB controls antigen presentation by major histocompatibility complexes (MHCs) in dendritic cells (Samie and Cresswell, 2015), suggesting a broad role for TFEB in controlling the immune response.…”

Section: Functional In Vivo Studies Of Tfebmentioning

confidence: 99%

TFEB at a glance

Napolitano

Ballabio

2016

Journal of Cell Science

593

637

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The transcription factor EB (TFEB) plays a pivotal role in the regulation of basic cellular processes, such as lysosomal biogenesis and autophagy. The subcellular localization and activity of TFEB are regulated by mechanistic target of rapamycin (mTOR)-mediated phosphorylation, which occurs at the lysosomal surface. Phosphorylated TFEB is retained in the cytoplasm, whereas dephosphorylated TFEB translocates to the nucleus to induce the transcription of target genes. Thus, a lysosome-to-nucleus signaling pathway regulates cellular energy metabolism through TFEB. Recently, in vivo studies have revealed that TFEB is also involved in physiological processes, such as lipid catabolism. TFEB has attracted a lot of attention owing to its ability to induce the intracellular clearance of pathogenic factors in a variety of murine models of disease, such as Parkinson's and Alzheimer's, suggesting that novel therapeutic strategies could be based on the modulation of TFEB activity. In this Cell Science at a Glance article and accompanying poster, we present an overview of the latest research on TFEB function and its implication in human diseases.

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Transcription factors TFE3 and TFEB are critical for CD40 ligand expression and thymus-dependent humoral immunity

Cited by 78 publications

References 55 publications

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis

TFEB at a glance

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