The essential clathrin adaptor protein complex-2 is tumor suppressive specifically in vivo
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PROVIDER: PRJNA975168 | ENA |
REPOSITORIES: ENA
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Project description:The microenvironment is a rich source of new cancer targets. While whole-genome CRISPR/Cas9 screens have identified vulnerabilities in cultured cells, it is a challenge to use this approach in tumors to interrogate the microenvironment. To this end, we screened a panel of pancreatic cancer lines grown in culture versus as tumors with a phosphatidylinositol metabolism CRISPR/Cas9 library. This revealed the Adaptor Protein complex-2 (AP2) of clathrin-mediated endocytosis behaves as common essential in culture but tumor suppressive in vivo. These polar-opposite phenotypes were attributed to different microenvironments. In culture, AP2 loss reduces endocytosis of transferrin and iron import. In tumors, alternative iron transport pathways allow pro-tumor signaling to manifest. In the most sensitive case, AP2 loss reprograms the plasma membrane proteome, retaining integrins on the surface leading to downregulation of the tumor-suppressor PTEN. Analysis of human tumors suggests a similar tumor suppressive activity. AP2 may foreshadow other proteins unique to the tumor-microenvironment.
2024-12-12 | GSE233173 | GEO
Project description:Mitochondrial complex III is essential for regulatory T cell suppressive function
| PRJNA493083 | ENA
Project description:Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis. Recent studies have demonstrated that Treg cells display a unique metabolic profile characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration; however, it remains unknown whether the mitochondrial respiratory chain is required for Treg cell suppressive capacity, stability, and survival. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III results in the development of a fatal inflammatory disease early in life, without impacting Treg cell number. Mice lacking complex III specifically in Treg cells displayed a loss of Treg cell suppressive capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III display decreased expression of genes associated with Treg function while maintaining stable FOXP3 expression. Complex III-null Treg cells displayed increased DNA methylation at the loci of differentially down-regulated genes without a global increase in DNA methylation. Loss of complex III in Treg cells resulted in buildup of the metabolites 2-hydroxyglutarate (2-HG) and succinate that can function as inhibitors of α-ketoglutarate (α−KG)-dependent dioxygenase reactions such as the ten-eleven translocation (TET) family of DNA demethylases. Thus, Treg cells require mitochondrial respiration to maintain immune regulatory gene expression and suppressive function.
2018-12-18 | GSE120451 | GEO
Project description:Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis. Recent studies have demonstrated that Treg cells display a unique metabolic profile characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration; however, it remains unknown whether the mitochondrial respiratory chain is required for Treg cell suppressive capacity, stability, and survival. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III results in the development of a fatal inflammatory disease early in life, without impacting Treg cell number. Mice lacking complex III specifically in Treg cells displayed a loss of Treg cell suppressive capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III display decreased expression of genes associated with Treg function while maintaining stable FOXP3 expression. Complex III-null Treg cells displayed increased DNA methylation at the loci of differentially down-regulated genes without a global increase in DNA methylation. Loss of complex III in Treg cells resulted in buildup of the metabolites 2-hydroxyglutarate (2-HG) and succinate that can function as inhibitors of α-ketoglutarate (α−KG)-dependent dioxygenase reactions such as the ten-eleven translocation (TET) family of DNA demethylases. Thus, Treg cells require mitochondrial respiration to maintain immune regulatory gene expression and suppressive function.
2018-12-18 | GSE120449 | GEO
Project description:Mitochondrial complex III is essential for regulatory T cell suppressive function. [DNA methylation/RRBS]
| PRJNA493088 | ENA
Project description:Mitochondrial complex III is essential for regulatory T cell suppressive function. [gene expression/RNA-seq]
| PRJNA493086 | ENA
Project description:IP of candidate adaptor Ada5/Gdi1, tagged with HA, versus Mock (untagged) replicates. IP associated RNA was assayed. A replicate experimental design type is where a series of replicates are performed to evaluate reproducibility or as a pilot study to determine the appropriate number of replicates for a subsequent experiments. GeneticModification: HA-tagged candidate gene or control replicate_design
2012-11-15 | E-GEOD-33747 | biostudies-arrayexpress
Project description:Analysis of the transcriptional correlates of FOXP3 expression in suppressive and non-suppressive primary human Treg cell clones. Individual CD4+CD25High or Cd4+CD25- T cells were isolated from human PBMCs and expanded in vitro. After 3 weeks of expansion, individual clones were analysed for FOXP3 expression and in vitro suppressive activity against freshly sorted allogeneic effector T cells. This study analyses the total RNA isolated from FOXP3+ clones with suppressive potency to their non-suppressive counterparts. The resutls of this study should provide insights into the molecular pathways linking FOXP3 expression to distinct aspects of Treg phenotype and function. Total RNA obtained from individual clones of primary human regulatory and effector CD4+T cells.
2015-05-06 | E-GEOD-65650 | biostudies-arrayexpress
Project description:IP of candidate adaptor Ada5/Gdi1, tagged with HA, versus Mock (untagged) replicates. IP associated RNA was assayed. A replicate experimental design type is where a series of replicates are performed to evaluate reproducibility or as a pilot study to determine the appropriate number of replicates for a subsequent experiments. GeneticModification: HA-tagged candidate gene or control
2012-11-15 | GSE33747 | GEO
Project description:The Microprocessor complex (DGCR8/Drosha) is required for microRNA (miRNA) biogenesis but also binds and regulates the stability of several types of cellular RNAs. Of particular interest, DGCR8 controls the stability of mature small nucleolar RNA (snoRNA) transcripts independently of Drosha, suggesting the existence of alternative DGCR8 complex/es with other nucleases to process a variety of cellular RNAs. Here, we found that DGCR8 co-purifies with subunits of the nuclear exosome, preferentially associating with its hRRP6-containing nucleolar form. Importantly, we demonstrate that DGCR8 is essential for the recruitment of the exosome to snoRNAs and to human telomerase RNA. In addition, we show that the DGCR8/exosome complex controls the stability of the human telomerase RNA component (hTR/TERC). Altogether, these data suggests that DGCR8 acts as a novel adaptor to recruit the exosome complex to structured RNAs and induce their degradation. [i] Examination of the RNA binding profile of hRRP6 (also known as EXOSC10) via iCLIP. [ii] HeLa cells were transiently depleted of hRRP6 or DGCR8 using siRNAs. For a control an non-targetting (siNon) siRNA was used. Three biological replicates of each samples were sent for RNA sequencing.
2015-12-10 | E-GEOD-73376 | biostudies-arrayexpress