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Project description:The mechanistic target of rapamycin complex 1 (mTORC1) controls cellular anabolism in response to nutrient sufficiency and growth factor signaling, and genetic and pharmacological inhibition of mTORC1 extends longevity across eukaryotes. Up to date, mouse models to analyze the mechanisms of aging governed by mTORC1 has been limited by detrimental pleiotropic consequences of genetically-increased mTORC1 activity in mice. RragcS74N/+, RragcS74C/+ and RragcT89N/+ knock-in mice endogenously express active mutant variants of RagC, a GTPase that signaling nutrient sufficiency to mTORC1. Rragcmutant/+ mice show an only moderate increase in nutrient signaling to mTORC1, and after one year of life exhibit multiple features of a premature aging phenotype that include prominent senescence in peripheral organs, parenchymal expression of inflammatory and chemo-attractant molecules, increased myeloid inflammation and extensive features of inflammaging. In vivo transplantation and ex vivo functional experiments with bone marrow-derived cells show that myeloid cells are abnormally activated by parenchymal signals evoked from Rragcmut/+ organs, to where myeloid cells extravasate to inflict additional inflammatory damage. Therapeutic suppression of myeloid inflammation in old Rragcmut/+ attenuates features of premature aging and extends longevity. We provide the first genetic link of elevated nutrient – mTORC1 activity and premature aging in mammals, and provide support for a two-component model in which increased nutrient signaling drives parenchymal damage and myeloid inflammation precipitates organ deterioration and accelerated aging.
2024-04-02 | GSE221286 | GEO
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) controls cellular anabolism in response to nutrient sufficiency and growth factor signaling, and genetic and pharmacological inhibition of mTORC1 extends longevity across eukaryotes. Up to date, mouse models to analyze the mechanisms of aging governed by mTORC1 has been limited by detrimental pleiotropic consequences of genetically-increased mTORC1 activity in mice. RragcS74N/+, RragcS74C/+ and RragcT89N/+ knock-in mice endogenously express active mutant variants of RagC, a GTPase that signaling nutrient sufficiency to mTORC1. Rragcmutant/+ mice show an only moderate increase in nutrient signaling to mTORC1, and after one year of life exhibit multiple features of a premature aging phenotype that include prominent senescence in peripheral organs, parenchymal expression of inflammatory and chemo-attractant molecules, increased myeloid inflammation and extensive features of inflammaging. In vivo transplantation and ex vivo functional experiments with bone marrow-derived cells show that myeloid cells are abnormally activated by parenchymal signals evoked from Rragcmut/+ organs, to where myeloid cells extravasate to inflict additional inflammatory damage. Therapeutic suppression of myeloid inflammation in old Rragcmut/+ attenuates features of premature aging and extends longevity. We provide the first genetic link of elevated nutrient – mTORC1 activity and premature aging in mammals, and provide support for a two-component model in which increased nutrient signaling drives parenchymal damage and myeloid inflammation precipitates organ deterioration and accelerated aging.
2024-04-02 | GSE221285 | GEO
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) controls cellular anabolism in response to nutrient sufficiency and growth factor signaling, and genetic and pharmacological inhibition of mTORC1 extends longevity across eukaryotes. Up to date, mouse models to analyze the mechanisms of aging governed by mTORC1 has been limited by detrimental pleiotropic consequences of genetically-increased mTORC1 activity in mice. RragcS74N/+, RragcS74C/+ and RragcT89N/+ knock-in mice endogenously express active mutant variants of RagC, a GTPase that signaling nutrient sufficiency to mTORC1. Rragcmutant/+ mice show an only moderate increase in nutrient signaling to mTORC1, and after one year of life exhibit multiple features of a premature aging phenotype that include prominent senescence in peripheral organs, parenchymal expression of inflammatory and chemo-attractant molecules, increased myeloid inflammation and extensive features of inflammaging. In vivo transplantation and ex vivo functional experiments with bone marrow-derived cells show that myeloid cells are abnormally activated by parenchymal signals evoked from Rragcmut/+ organs, to where myeloid cells extravasate to inflict additional inflammatory damage. Therapeutic suppression of myeloid inflammation in old Rragcmut/+ attenuates features of premature aging and extends longevity. We provide the first genetic link of elevated nutrient – mTORC1 activity and premature aging in mammals, and provide support for a two-component model in which increased nutrient signaling drives parenchymal damage and myeloid inflammation precipitates organ deterioration and accelerated aging.
2024-04-02 | GSE221284 | GEO
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) controls cellular anabolism in response to nutrient sufficiency and growth factor signaling, and genetic and pharmacological inhibition of mTORC1 extends longevity across eukaryotes. Up to date, mouse models to analyze the mechanisms of aging governed by mTORC1 has been limited by detrimental pleiotropic consequences of genetically-increased mTORC1 activity in mice. RragcS74N/+, RragcS74C/+ and RragcT89N/+ knock-in mice endogenously express active mutant variants of RagC, a GTPase that signaling nutrient sufficiency to mTORC1. Rragcmutant/+ mice show an only moderate increase in nutrient signaling to mTORC1, and after one year of life exhibit multiple features of a premature aging phenotype that include prominent senescence in peripheral organs, parenchymal expression of inflammatory and chemo-attractant molecules, increased myeloid inflammation and extensive features of inflammaging. In vivo transplantation and ex vivo functional experiments with bone marrow-derived cells show that myeloid cells are abnormally activated by parenchymal signals evoked from Rragcmut/+ organs, to where myeloid cells extravasate to inflict additional inflammatory damage. Therapeutic suppression of myeloid inflammation in old Rragcmut/+ attenuates features of premature aging and extends longevity. We provide the first genetic link of elevated nutrient – mTORC1 activity and premature aging in mammals, and provide support for a two-component model in which increased nutrient signaling drives parenchymal damage and myeloid inflammation precipitates organ deterioration and accelerated aging.
2024-04-02 | GSE221283 | GEO
Project description:The Rag guanosine triphosphatases (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-electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC 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 of RagA/RagC 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.
| S-EPMC6795536 | biostudies-literature
Project description:Amino acids stimulate cell growth and suppress autophagy through activation of mTORC1. The activation of mTORC1 by amino acids is mediated by Rag guanosine triphosphatase (GTPase) heterodimers on the lysosome. The molecular mechanism by which amino acids regulate the Rag GTPase heterodimers remains to be elucidated. Here, we identify SH3 domain-binding protein 4 (SH3BP4) as a binding protein and a negative regulator of Rag GTPase complex. SH3BP4 binds to the inactive Rag GTPase complex through its Src homology 3 (SH3) domain under conditions of amino acid starvation and inhibits the formation of active Rag GTPase complex. As a consequence, the binding abrogates the interaction of mTORC1 with Rag GTPase complex and the recruitment of mTORC1 to the lysosome, thus inhibiting amino acid-induced mTORC1 activation and cell growth and promoting autophagy. These results demonstrate that SH3BP4 is a negative regulator of the Rag GTPase complex and amino acid-dependent mTORC1 signaling.
| S-EPMC3389276 | biostudies-literature
Project description:Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2 but also in the absence of AMPK. Consistent with these observations, in two distinct preclinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.
| S-EPMC3081779 | biostudies-literature
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell survival and autophagy, and its activity is regulated by amino acid availability. Rag GTPase-GATOR1 interactions inhibit mTORC1 in the absence of amino acids, and GATOR1 release and activation of RagA/B promotes mTORC1 activity in the presence of amino acids. However, the factors that play a role in Rag-GATOR1 interaction are still poorly characterized. Here, we show that the tyrosine kinase Src is crucial for amino acid-mediated activation of mTORC1. Src acts upstream of the Rag GTPases by promoting dissociation of GATOR1 from the Rags, thereby determining mTORC1 recruitment and activation at the lysosomal surface. Accordingly, amino acid-mediated regulation of Src/mTORC1 modulates autophagy and cell size expansion. Finally, Src hyperactivation overrides amino acid signaling in the activation of mTORC1. These results shed light on the mechanisms underlying pathway dysregulation in many cancer types.
| S-EPMC6195609 | biostudies-literature
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:A key step in nutrient sensing is activation of the master growth regulator, mTORC1 kinase, on the lysosomal membrane. Nutrients enable mTORC1 scaffolding by a complex composed of the Rag GTPases (Rags) and Ragulator, but the underlying mechanism of mTORC1 capture is poorly understood. Combining dynamic imaging in cells and reconstituted systems, we uncover an affinity switch that controls mTORC1 lifetime and activation at the lysosome. Nutrients destabilize the Rag-Ragulator interface, causing cycling of the Rags between lysosome-bound Ragulator and the cytoplasm, and rendering mTORC1 capture contingent on simultaneous engagement of two Rag-binding interfaces. Rag GTPase domains trigger cycling by coordinately weakening binding of the C-terminal domains to Ragulator in a nucleotide-controlled manner. Cancer-specific Rag mutants override release from Ragulator and enhance mTORC1 recruitment and signalling output. Cycling in the active state sets the Rags apart from most signalling GTPases, and provides a mechanism to attenuate mTORC1 signalling.
| S-EPMC6279252 | biostudies-literature