Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1

ABSTRACT: mTORC1 is a nutrient sensor which integrates diverse inputs to regulate protein translation and cell growth. While mTORC1 is activated on the lysosome in the classical model, it has become increasingly clear that this multifaceted signaling complex is active at various subcellular locations, such as the nucleus. However, what specific functions mTORC1 serves at these locations and how its signaling is compartmentalized are not unclear. To interrogate subcellular pools of mTORC1, we developed TerminaTOR, a genetically encodable inhibitor of mTORC1 that can be targeted to specific subcellular locations. When TerminaTOR is directed to the lysosome, it inhibits canonical lysosomal mTORC1 and induces autophagy. Furthermore, TerminaTOR targeted to the nucleus specifically inhibits nuclear mTORC1, uncovering non-canonical roles of nuclear mTORC1 in regulating the transcription of CCAAT motif-containing genes. Thus, mTORC1 exhibits functional spatial compartmentalization, and TerminaTOR serves as a powerful tool for unraveling spatially regulated functions of mTORC1 across different scales

ORGANISM(S): Mus musculus

PROVIDER: GSE320090 | GEO | 2026/02/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The Protein Complex Ragulator is the Substrate-specific Scaffold for mTORC1 to Regulate Transcription Factor EB

Project description:Mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is activated by nutrition sufficiency signals and extracellular growth signals. mTORC1 acts the hub that integrates these inputs to orchestrate number of cellular responses such as translation, nucleotide synthesis, lipid synthesis, and lysosome biogenesis. However, the scaffold protein which specifically regulates any single downstream signaling molecule has not been identified to date. Here we show the heteropentamer protein complex Ragulator is critically required to regulate nuclear translocation of transcription factor EB (TFEB). We established a unique RAW264.7 clone that lacks Ragulator but maintained total mTORC1 activity. The clone showed a markedly enhanced nuclear translocation of TFEB even in nutrition-sufficient state, despite the full mTORC1 activity. As a cellular phenotype, the number of lysosomes were increased by 10 times in the Ragulator-deficient clone. These findings suggest that mTORC1 essentially requires the scaffold Ragulator to regulate the subcellular location of TFEB. Our finding implicates that mTORC1 has other scaffold proteins that regulate downstream molecules specifically.

2021-08-08 | GSE171357 | GEO

ArfGAP1 inhibits mTORC1 lysosomal localization and activation

Project description:The mammalian target of rapamycin complex 1 (mTORC1) integrates nutrients, growth factors, stress, and energy status to regulate cell growth and metabolism. Amino acids promote mTORC1 lysosomal localization and subsequent activation. However, the subcellular location or interacting proteins of mTORC1 under amino acid deficient conditions is not completely understood. Here, we identify ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1) as a crucial regulator of mTORC1. ArfGAP1 interacts with mTORC1 in the absence of amino acids and inhibits mTORC1 lysosomal localization and activation. Mechanistically, the membrane curvature sensing amphipathic lipid packing sensor (ALPS) motifs that bind to vesicle membranes, are crucial for ArfGAP1 to interact with and regulate mTORC1 activity. Importantly, ArfGAP1 represses cell growth through mTORC1 and is an independent prognostic factor for the overall survival of pancreatic cancer patients. Our study identifies ArfGAP1 as a critical regulator of mTORC1 that functions by preventing the lysosomal transport and activation of mTORC1, with potential for cancer therapeutics.

2021-04-01 | PXD024603 | Pride

Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization (Microarray)

Project description:Differentiation is critical for epithelial cell fate decisions, but the signals involved remain unclear. The kidney proximal tubule (PT) cells reabsorb disulphide-rich proteins through endocytosis, generating cystine via lysosomal proteolysis. Here we report that defective cystine mobilization from lysosomes through cystinosin (CTNS), which is mutated in cystinosis, diverts PT cells towards growth and proliferation, disrupting their functions. Mechanistically, lysosomal cystine storage stimulates Ragulator-Rag GTPase-dependent recruitment of mechanistic target of Rapamycin complex 1 (mTORC1) and its constitutive activation. Re-introduction of CTNS restores nutrient-dependent regulation of mTORC1 in knockout cells, whereas cell-permeant analogues of L-cystine, accumulating within lysosomes, render wild-type cells resistant to nutrient withdrawal. Therapeutic mTORC1 inhibition corrects lysosome and differentiation downstream of cystine storage, and phenotypes in a zebrafish model of cystinosis. Thus, cystine serves as a lysosomal signal that tailors mTORC1 signaling and metabolism to direct epithelial cell fate decisions. These results identify mechanisms and therapeutic targets for dysregulated homeostasis in cystinosis.

2023-03-08 | GSE226396 | GEO

Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization (RNA-Seq)

2023-03-08 | GSE226397 | GEO

Quantitative Phosphoproteomic Analyses Identify STK11IP as a Lysosome-Specific Substrate of mTORC1 that Regulates Lysosomal Acidification

Project description:The evolutionarily conserved serine/threonine kinase mTORC1 is a central regulator of cell growth and proliferation. mTORC1 is activated on the lysosome surface. However, once mTORC1 is activated, it is unclear whether mTORC1 phosphorylates local lysosomal proteins to regulate specific aspects of lysosomal biology. By integrating analyses of lysosome proteome with mTORC1-regulated phosphoproteome, we identify STK11IP as a lysosome-specific substrate of mTORC1. mTORC1 phosphorylates STK11IP at S404. Knockout of STK11IP leads to a robust increase of autophagy flux. Dephosphorylation of STK11IP at S404 represses the role of STK11IP as an autophagy inhibitor. Mechanistically, STK11IP binds to V-ATPase, and regulates the activity of V-ATPase. Knockout of STK11IP protects mice from fasting or Methionine/Choline-Deficient Diet diet-induced fatty liver. Thus, our study demonstrates that STK11IP phosphorylation represents a novel mechanism for mTORC1 to regulate lysosomal acidification and autophagy, and points to STK11IP as a promising therapeutic target for the amelioration of diseases with aberrant autophagy signaling.

2022-05-20 | PXD031543 | Pride

mTORC1 regulates GRASP55-dependent unconventional secretion in response to stress

Project description:In cells, several cargoes are delivered to the cell surface or the extracellular space via unconventional secretion routes. GRASP55 is a Golgi protein that regulates unconventional secretion of distinct proteins and controls the assembly and membrane stacking of Golgi cisternae. Recent work suggested that the role of GRASP55 in unconventional secretion may involve its relocalization to other organelles. However, the stimuli that drive GRASP55-dependent unconventional secretion, the signaling events that regulate GRASP55 function, the subcellular locations where GRASP55 acts, and the cargoes that follow this route for secretion remain unclear. Here, we show that mTORC1 directly phosphorylates GRASP55 at multiple sites to maintain its Golgi localization. Cellular stresses or drugs that inhibit mTORC1 cause GRASP55 dephosphorylation and relocalization to autophagosomal / MVB structures. Using secretome and surfactome analyses in GRASP55-null cells, we identify for the first time numerous -previously unknown- cargoes that rely on this unconventional secretory pathway.

2021-09-09 | PXD020331 | Pride

Lysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization, proteomics-based profiling of Ctns KO mouse proximal tubule cells (mPTCs)

2025-05-13 | PXD040450 | Pride

mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes

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

Reversing lysosome-mTORC1-ribosome axis dysregulations to mitigate C9FTD/ALS neurodegeneration

Project description:Reversing lysosome-mTORC1-ribosome axis dysregulations to mitigate C9FTD/ALS neurodegeneration

| PRJNA851737 | ENA

ATR promotes mTORC1 activity via de novo cholesterol synthesis

Project description:DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback mechanisms. Key mediators of the DNA damage response and cellular metabolic regulation include Ataxia Telangiectasia and Rad3-related protein (ATR) and the mechanistic Target of Rapamycin Complex 1 (mTORC1), respectively. Previous studies have established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms by which mTORC1 is activated in this context remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. Here, we demonstrate that ATR promotes mTORC1 activity across various cellular models under basal conditions. This effect is particularly enhanced in cells following the loss of p16, which we have previously associated with hyperactivation of mTORC1 signaling and here found increased ATR activity. Mechanistically, we found that ATR promotes de novo cholesterol synthesis and mTORC1 activation through the upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Furthermore, the attenuation of mTORC1 activity resulting from ATR inhibition was rescued by supplementation with lanosterol or cholesterol in multiple cellular con-texts. This restoration corresponded with enhanced localization of mTOR to the lysosome. Collectively, our findings link ATR and mTORC1 signaling through the modulation of cholesterol metabolism.

2025-04-01 | PXD061265 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data