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Amino acid licensing of regulatory T cell function requires signaling via small G proteins Rag and Rheb

ABSTRACT: Amino acid licensing of regulatory T cell function requires signaling via small G proteins Rag and Rheb

PROVIDER: PRJNA559891 | ENA |

REPOSITORIES: ENA

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Amino acid licensing of regulatory T cell function requires signaling via small G proteins Rag and Rheb

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

Architecture of human Rag GTPase heterodimers and their complex with mTORC1

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

Distinctive responses to nitrogen starvation in the dominant active mutants of the fission yeast Rheb GTPase.

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

Distinctive responses to nitrogen starvation in the dominant active mutants of the fission yeast Rheb GTPase.

2009-09-29 | GSE14626 | GEO

Effect of Rheb depletion of Rheb and Ribo-HA knock-in on gene expression of neurons

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

Microarray on T-Rheb -/- CD4+ and CD8+ cells

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

genes differentially expressed in brown adipose tissue between the control mice (rheb FL/FL) and rheb BAD KO mice (Ucp1-cre; rheb FL/FL)

Project description:RNA sequencing was performed to analyze expression profile in brown adipose tissue with or without rheb knockout.

2021-10-21 | GSE186093 | GEO

RNA-seq analysis of pro-B cells from RAG, double RAG/Emu, double RAG/3'RR and double RAG/KOKI deficient mice.

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

TSC-Insensitive Rheb Mutations Induce Oncogenic Transformation Through a Combination of Hyperactive mTORC1 Signalling and Metabolic Reprogramming

Project description:The mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cellular metabolism that is commonly hyperactivated in cancer. Recent cancer genome screens have identified multiple mutations in Ras-homolog enriched in brain (Rheb), the primary activator of mTORC1, that might act as driver oncogenes through aberrant hyperactivation of mTORC1. Here, we show that a number of recurrently occurring Rheb mutants drive hyperactive mTORC1 signalling through differing levels of insensitivity to the primary inactivator of Rheb, Tuberous Sclerosis Complex. We show that two activated mutants, Rheb-T23M and E40K, strongly drive increased cell growth and proliferation and anchorage-independent growth resulting in enhanced tumour growth in vivo. Proteomic analysis of cells expressing the mutations revealed, surprisingly, that these two mutants promote distinct oncogenic pathways with Rheb-T23M driving metabolic reprogramming and an increased reliance of glycolysis, while Rheb-E40K interacts with AMPK to regulate eukaryotic elongation factor 2 (eEF2) and autophagy. Our findings suggest that unique ‘bespoke’ combination therapies may be utilised to treat cancers according to which Rheb mutant they harbour.

2021-04-22 | PXD017006 | Pride