Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis

Kaiser, Marco S. and Milan, Giulia and Lin, Shuo and Oliveri, Filippo and Chojnowska, Kathrin and Tintignac, Lionel A. and Mittal, Nitish and Zimmerli, Christian E. and Glass, David J. and Zavolan, Mihaela and Ham, Daniel J. and Rüegg, Markus A.. (2021) Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis. bioRxiv. pp. 1-39.

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Muscle size is controlled by the PI3K-PKB/Akt-mTORC1-FoxO pathway, which integrates signals from growth factors, energy and amino acids to activate protein synthesis and inhibit protein breakdown. While mTORC1 activity is necessary for PKB/Akt-induced muscle hypertrophy, its constant activation alone induces muscle atrophy. Here we show that this paradox is based on mTORC1 activity promoting protein breakdown through the ubiquitin-proteasome system (UPS) by simultaneously inducing ubiquitin E3 ligase expression via feedback inhibition of PKB/Akt and proteasome biogenesis via Nuclear Factor Erythroid 2-Like 1 (Nrf1). Muscle growth was restored by reactivation of PKB/Akt, but not by Nrf1 knockdown, implicating ubiquitination as the limiting step. However, both PKB/Akt activation and proteasome depletion by Nrf1 knockdown led to an immediate disruption of proteome integrity with rapid accumulation of damaged material. These data highlight the physiological importance of mTORC1-mediated PKB/Akt inhibition and point to juxtaposed roles of the UPS in atrophy and proteome integrity.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A.
Item Type:Article
Article Subtype:Research Article
Publisher:Cold Spring Harbor Laboratory
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:28 Mar 2022 14:46
Deposited On:03 Mar 2022 15:51

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