Amino acid licensing of regulatory T cell function requires signaling via small G proteins Rag and Rheb
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PROVIDER: PRJNA559891 | ENA |
REPOSITORIES: ENA
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Project description:Amino acids license Treg cell function by priming and sustaining TCR induced mTORC1 activity and Rag and Rheb GTPases as central regulators of mTORC1 activation in effector Treg (eTreg) cells RNA was purified from CD25+ Treg cells isolated from Cd4CreRragafl/flRragabfl/fl or Cd4CreRhebfl/flRhebl1–/– mice or their littermate controls.
2019-11-04 | GSE135739 | GEO
Project description:The Rag GTPases recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo-EM structure of RagA/RagC in complex with mTORC1 shows the details of RagA/C binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDP nucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics show the mechanism for this locking, and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.
2019-10-11 | PXD015778 | Pride
Project description:Rheb, a ras-like small GTPase conserved from human to yeast, controls Tor kinase and plays a central role in regulation of cell growth depending on extracellular conditions. Fission yeast Rheb regulates amino acid uptake as well as response to nitrogen starvation. In this study we generated two mutants of Rheb, rhb1-DA4 and rhb1-DA8, and characterized them genetically. V17A mutation within the G1 box defined for the ras-like GTPases was responsible for rhb1-DA4, and Q52R I76F within the switch II domain for rhb1-DA8. In fission yeast, two events, induction of a meiosis initiating gene mei2+ and cell division without cell growth, are a typical response to nitrogen starvation. Under nitrogen-rich conditions, Rheb stimulates Tor kinase, which, in turn, suppresses the response to nitrogen starvation. While amino acid uptake was prevented by both rhb1-DA4 and rhb1-DA8 in a dominant fashion, the response to nitrogen starvation was prevented only by rhb1-DA4. rhb1-DA8 thereby allowed genetic dissection of the Rheb-dependent signaling cascade. We postulate that Rheb in fission may have two downstream elements, Tor kinase for regulation of the response to nitrogen starvation and the other element for regulation of amino acid uptake. Gene expression profile under nitrogen starvation in fission yeast. Type of experiment: Comparing between vegetatively-growing control cells and cells 3 hrs after nitrogen starvation. Experimental factor: Gene expression profile after nitrogen starvation in the rhb1-D4 or rhb1-D8 cells. Quality control steps taken: All experiments were repeated more than twice except for the tsc2D which was previously reported. Keywards: Nitrogen starvation, rhb1-D4, rhb1-D8
2009-09-28 | E-GEOD-14626 | biostudies-arrayexpress
Project description:Rheb, a ras-like small GTPase conserved from human to yeast, controls Tor kinase and plays a central role in regulation of cell growth depending on extracellular conditions. Fission yeast Rheb regulates amino acid uptake as well as response to nitrogen starvation. In this study we generated two mutants of Rheb, rhb1-DA4 and rhb1-DA8, and characterized them genetically. V17A mutation within the G1 box defined for the ras-like GTPases was responsible for rhb1-DA4, and Q52R I76F within the switch II domain for rhb1-DA8. In fission yeast, two events, induction of a meiosis initiating gene mei2+ and cell division without cell growth, are a typical response to nitrogen starvation. Under nitrogen-rich conditions, Rheb stimulates Tor kinase, which, in turn, suppresses the response to nitrogen starvation. While amino acid uptake was prevented by both rhb1-DA4 and rhb1-DA8 in a dominant fashion, the response to nitrogen starvation was prevented only by rhb1-DA4. rhb1-DA8 thereby allowed genetic dissection of the Rheb-dependent signaling cascade. We postulate that Rheb in fission may have two downstream elements, Tor kinase for regulation of the response to nitrogen starvation and the other element for regulation of amino acid uptake.
2009-09-29 | GSE14626 | GEO
Project description:To examine the effect of neuronal Rheb on brain myelination, we generated a conditional neuronal Rheb knockout mouse line.
2023-05-31 | GSE230354 | GEO
Project description:A microarray was performed on T-Rheb -/- (CD4 cre positive Rheb fl/fl) and Wt C57B6J CD4+ and CD8+ cells. T-Rheb -/- mice had reduced fasting blood glucose and we were interested to see if there was a difference in the T cells that could mediate our phenotype.
2021-01-01 | GSE156529 | GEO
Project description:To stimulate cell growth, the protein kinase complex mTORC1 requires intracellular amino acids for activation. Amino-acid sufficiency is relayed to mTORC1 by Rag GTPases on lysosomes, where growth factor signaling enhances mTORC1 activity via the GTPase Rheb. In the absence of amino acids, GATOR1 inactivates the Rags, resulting in lysosomal detachment and inactivation of mTORC1. We demonstrate that in human cells, the release of mTORC1 from lysosomes depends on its kinase activity. In accordance with a negative feedback mechanism, activated mTOR mutants display low lysosome occupancy, causing hypo-phosphorylation and nuclear localization of the lysosomal substrate TFE3. Surprisingly, mTORC1 activated by Rheb does not increase the cytoplasmic/lysosomal ratio of mTORC1, indicating the existence of mTORC1 pools with distinct substrate specificity. Dysregulation of either pool results in aberrant TFE3 activity and may explain nuclear accumulation of TFE3 in epileptogenic malformations in focal cortical dysplasia type II (FCD II) and tuberous sclerosis (TSC).
2024-11-26 | PXD043611 | Pride
Project description:RNA sequencing was performed to analyze expression profile in brown adipose tissue with or without rheb knockout.
2021-10-21 | GSE186093 | GEO
Project description:By their impact on nuclear organisation, enhancers are master regulators of cell fate. We thus developed double Emu-RAG-deficient, 3’RR-RAG-deficient mice and KOKI-RAG-deficient mice to investigate a potential transcriptional cross-talk between Emu and 3'RR enhancers at the pro-B cell stage.
2019-02-07 | GSE117449 | GEO
Project description:Regulatory T (Treg) cells are critical mediators of immune tolerance whose activity depends upon T cell receptor (TCR) and mTORC1 kinase signaling, but the mechanisms that dictate functional activation of these pathways are incompletely understood. Here, we showed that amino acids license Treg cell function by priming and sustaining TCR-induced mTORC1 activity. mTORC1 activation was induced by amino acids, especially arginine and leucine, accompanied by the dynamic lysosomal localization of the mTOR and Tsc complexes. Rag and Rheb GTPases were central regulators of amino acid-dependent mTORC1 activation in effector Treg (eTreg) cells. Mice bearing RagA-RagB- or Rheb1-Rheb2-deficient Treg cells developed a fatal autoimmune disease and had reduced eTreg cell accumulation and function. RagA-RagB regulated mitochondrial and lysosomal fitness, while Rheb1-Rheb2 enforced eTreg cell suppressive gene signature. Together, these findings reveal a crucial requirement of amino acid signaling for licensing and sustaining mTORC1 activation and functional programming of Treg cells.
| S-EPMC6948188 | biostudies-literature