Amino Acid-Mediated Intracellular Ca2+ Rise Modulates mTORC1 by Regulating the TSC2-Rheb Axis through Ca2+/Calmodulin
| Autor: | Nao Nakamura, Nao Ikeda, Hideki Shibata, Yuna Amemiya, Chiaki Ishii, Risa Sugiyama, Masatoshi Maki, Terunao Takahara |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Rheb GTPase
calmodulin GTPase-activating protein Calmodulin QH301-705.5 Intracellular Space GTPase mTORC1 Mechanistic Target of Rapamycin Complex 1 Models Biological Catalysis Article Cell Line Inorganic Chemistry Tuberous Sclerosis Complex 2 Protein Protein biosynthesis Humans Calcium Signaling Physical and Theoretical Chemistry Amino Acids Biology (General) Molecular Biology QD1-999 Spectroscopy TSC chemistry.chemical_classification calcium biology Chemistry Activator (genetics) Organic Chemistry General Medicine Computer Science Applications Cell biology Amino acid Gene Knockdown Techniques biology.protein mTOR Ras Homolog Enriched in Brain Protein biological phenomena cell phenomena and immunity Lysosomes amino acid RHEB Protein Binding Signal Transduction |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 6897, p 6897 (2021) International Journal of Molecular Sciences Volume 22 Issue 13 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | Mechanistic target of rapamycin complex 1 (mTORC1) is a master growth regulator by controlling protein synthesis and autophagy in response to environmental cues. Amino acids, especially leucine and arginine, are known to be important activators of mTORC1 and to promote lysosomal translocation of mTORC1, where mTORC1 is thought to make contact with its activator Rheb GTPase. Although amino acids are believed to exclusively regulate lysosomal translocation of mTORC1 by Rag GTPases, how amino acids increase mTORC1 activity besides regulation of mTORC1 subcellular localization remains largely unclear. Here we report that amino acids also converge on regulation of the TSC2-Rheb GTPase axis via Ca2+/calmodulin (CaM). We showed that the amino acid-mediated increase of intracellular Ca2+ is important for mTORC1 activation and thereby contributes to the promotion of nascent protein synthesis. We found that Ca2+/CaM interacted with TSC2 at its GTPase activating protein (GAP) domain and that a CaM inhibitor reduced binding of CaM with TSC2. The inhibitory effect of a CaM inhibitor on mTORC1 activity was prevented by loss of TSC2 or by an active mutant of Rheb GTPase, suggesting that a CaM inhibitor acts through the TSC2-Rheb axis to inhibit mTORC1 activity. Taken together, in response to amino acids, Ca2+/CaM-mediated regulation of the TSC2-Rheb axis contributes to proper mTORC1 activation, in addition to the well-known lysosomal translocation of mTORC1 by Rag GTPases. |
| Databáze: | OpenAIRE |
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