The identification of the Rag GTPases initiated the deciphering of the molecular puzzle of nutrient signaling to the mechanistic target of rapamycin (mTOR), and spurred interest in targeting this pathway to combat human disease. Recent mouse genetic studies have provided pathophysiological insight and pointed to potential indications for inhibitors of the Rag GTPase pathway.
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http://dx.doi.org/10.1080/23723556.2021.1979370 | DOI Listing |
Immunity
December 2024
Department of Thoracic Surgery of Sir Run Run Shaw Hospital, and Department of Biochemistry, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China. Electronic address:
Induction of autophagy is an ancient function of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway through which autophagic cargoes are delivered to lysosomes for degradation. However, whether lysosome function is also modulated by the cGAS-STING pathway remains unknown. Here, we discovered that the cGAS-STING pathway upregulated lysosomal activity by stimulating lysosome biogenesis independently of the downstream protein kinase TANK-binding kinase 1 (TBK1).
View Article and Find Full Text PDFbioRxiv
November 2024
Department of Molecular and Cell Biology, University of California Berkeley; Berkeley CA 94720, USA.
Mechanistic target of rapamycin complex 1 (mTORC1), which consists of mTOR, Raptor, and mLST8, receives signaling inputs from growth factor signals and nutrients. These signals are mediated by the Rheb and Rag small GTPases, respectively, which activate mTORC1 on the cytosolic face of the lysosome membrane. We biochemically reconstituted the activation of mTORC1 on membranes by physiological submicromolar concentrations of Rheb, Rags, and Ragulator.
View Article and Find Full Text PDFNat Commun
November 2024
Division of Rheumatology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN, USA.
Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined.
View Article and Find Full Text PDFCells
October 2024
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Cell
November 2024
Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands. Electronic address:
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.
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