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SMAD4 plays acritical role in CD8 T cell cytotoxic function [ChIP-seq]

ABSTRACT: SMAD4 plays acritical role in CD8 T cell cytotoxic function [ChIP-seq]

PROVIDER: PRJNA792408 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17332686.fastq.gz	Fastqsanger.gz
	SRR17332687.fastq.gz	Fastqsanger.gz

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SMAD4 plays acritical role in CD8 T cell cytotoxic function

Project description:SMAD4 plays acritical role in CD8 T cell cytotoxic function

| PRJNA792409 | ENA

SMAD4 plays acritical role in CD8 T cell cytotoxic function [RNA-seq]

Project description:Transforming growth factor-beta (TGF-β) restrains cytotoxic immune response to maintain self-tolerance and to promote tumor immune evasion. Yet how SMAD4, a central transcription factor component of TGF-β signaling, regulates CD8+ T cell function remains unclear. Here we have demonstrated SMAD4 played a critical role in promoting CD8+ T cell activation and cytotoxic function. SMAD4-mediated transcriptional regulation of CD8+ T cell activation and cytotoxicity is regulated by T-cell receptor (TCR) signaling pathway rather than TGF-β signaling pathway. We described a new mechanism that in TCR-mediated intracellular signal propagation, SMAD4 markedly translocated into the nucleus, upregulated genes that encoding TCR complex subunits and cytotoxic molecules in CD8+ T cells, reinforced the TCR-activation signals through a positive feedback loop. And in this signaling, SMAD4 is phosphorylated by ERK at Ser367 residue. Our study thus demonstrates an essential role of SMAD4 in promoting CD8+ T cell mediated cytotoxic immune responses.

2022-07-12 | GSE192621 | GEO

SMAD4 plays acritical role in CD8 T cell cytotoxic function [ChIP-seq]

2022-07-12 | GSE192620 | GEO

SMAD4 plays acritical role in CD8 T cell cytotoxic function [RNA-seq]

Project description:SMAD4 plays acritical role in CD8 T cell cytotoxic function [RNA-seq]

| PRJNA792411 | ENA

SMAD4 plays acritical role in CD8 T cell cytotoxic function

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-07-12 | GSE192622 | GEO

TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation [ChIPseq]

Project description:SMAD4, a key mediator of TGF-beta signaling, plays a crucial role in T cells to prevent chronic intestinal inflammation through unknown mechanisms. We reveal that SMAD4 in CD8 T cells prevents chronic intestinal inflammation primarily in a TGF-beta-independent manner. Mechanistically, SMAD4, in CD8 T cells, acts as a basal and tonic repressor of TGF-beta-target genes at the transcriptional and epigenetic level, prior to any TGF-beta signal. SMAD4 deletion affects aberrantly a wide range of TGF-beta-target genes, thereby promoting accumulation and epithelial retention of CD8.alpha.beta T cells inversely to total TGF-beta signaling disruption. Moreover, SMAD4 deletion unleashes the expression of TGF-beta-signaling-repressors and hampers TGF-β-mediated CD8 T cell immunosuppression, eliciting their chronic activation. Hence, in a feedforward mechanism, SMAD4 both blocks the TGF-beta signature in CD8 T cells and pre-sensitizes them to TGF-beta.

2022-03-15 | GSE188932 | GEO

TGF-beta-independent function of SMAD4 preconditions naïve CD8 T-cells to prevent severe microbiota-driven chronic intestinal inflammation [RNAseq]

2022-03-15 | GSE188933 | GEO

Comparision of expression profile between CD4+ helper T cells and CD8+ cytotoxic T cells

Project description:We compared gene expression profiling between CD4+ helper T cells and CD8+ cytotoxic T cells CD4+ helper T cells vs CD8+ cytotoxic T cells

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SMAD4-NFATc1 protein-protein interaction informed therapeutic vulnerability in SMAD4-deficient pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a median survival rate of approximately six months. While genetic profiling has uncovered common mutations in PDAC, developing targeted therapeutic strategies remains challenging. SMAD4 is frequently mutated or deleted in 30-55% of PDAC patients and correlates with poor survival rates. Such mutations frequently result in loss-of-function, thereby disrupting normal cell cycle regulation and contributing to tumorigenesis. Therefore, translating SMAD4 genotype into actionable targets are highly desired for therapeutic innovation in PDAC. In this study, we performed a SMAD4-focused oncogenic protein-protein interaction (oncoPPI) network mapping and revealed a direct physical interaction between SMAD4 and NFATc1. We found that SMAD4 interacts with NFATc1 in a TGF-independent and NFATc1 phosphorylation-dependent manner. Further, SMAD4 sequesters NFATc1 in cytoplasm and inhibits NFATc1 transcriptional activity. In PDAC cells, SMAD4-loss releases its inhibitory activity on NFATc1, activates NFATc1 transcriptional activity which drives STAT3 mRNA and protein upregulation. Pharmacological profiling identified multiple STAT3 inhibitors selectively inhibit the growth of SMAD4-loss PDAC cells. These results suggested a rewired SMAD4-NFATc1-STAT3 axis and targeting STAT3 as a potential therapeutic strategy in SMAD4-loss PDAC.

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Project description:Glucose is essential for T cell proliferation and function, yet the metabolic fates of glucose critical for T cell responses in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as an essential arm of glucose metabolism that fuels CD8+ T cell expansion and cytotoxic function in vivo. Using stable isotope tracing, we show that CD8+ effector T (Teff) cells in vivo use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a common precursor for glycogen, glycan, and GSL biosynthesis. Blocking GSL production–by targeting the enzymes UDP-Glc pyrophosphorylase 2 (UGP2) or UDP-Glc ceramide glucosyltransferase (UGCG)–blunts CD8+ T cell expansion and cytotoxic activity without impacting glucose-dependent energy production. Mechanistically, we show that glucose-dependent GSL biosynthesis (via UGCG) maintains lipid integrity at the plasma membrane and is required for lipid raft aggregation following T cell receptor (TCR) stimulation. CD8+ T cells lacking UGCG display poor cytotoxic function and reduced tumor control in vivo. Together, our data highlight GSL biosynthesis as an essential metabolic fate for glucose–independent of energy production–required to maintain membrane lipid homeostasis and CD8+ T cell cytotoxic function in vivo.

2025-08-08 | PXD056453 | Pride

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