Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation
- University of Fribourg, Switzerland
- University of Milano-Bicocca, Italy
- University of Freiburg, Germany
- KU Leuven, Belgium
Abstract
The AMP-activated protein kinase (AMPK) and the target of rapamycin complex 1 (TORC1) are central kinase modules of two opposing signaling pathways that control eukaryotic cell growth and metabolism in response to the availability of energy and nutrients. Accordingly, energy depletion activates AMPK to inhibit growth, while nutrients and high energy levels activate TORC1 to promote growth. Both in mammals and lower eukaryotes such as yeast, the AMPK and TORC1 pathways are wired to each other at different levels, which ensures homeostatic control of growth and metabolism. In this context, a previous study (Hughes Hallet et. al, 2015) reported that AMPK in yeast, i.e. Snf1, prevents the transient TORC1 reactivation during the early phase following acute glucose starvation, but the underlying mechanism has remained elusive. Using a combination of unbiased mass spectrometry (MS)-based phosphoproteomics, genetic, biochemical, and physiological experiments, we show here that Snf1 temporally maintains TORC1 inactive in glucose-starved cells primarily through the TORC1-regulatory protein Pib2. Our data, therefore, extend the function of Pib2 to a hub that integrates both glucose and, as reported earlier, glutamine signals to control TORC1. We further demonstrate that Snf1 phosphorylates the TORC1 effector kinase Sch9 within its N-terminal region and thereby antagonizes the phosphorylation of a C-terminal TORC1-target residue within Sch9 itself that is critical for its activity. The consequences of Snf1-mediated phosphorylation of Pib2 and Sch9 are physiologically additive and sufficient to explain the role of Snf1 in short-term inhibition of TORC1 in acutely glucose-starved cells.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-6 and Supplementary figures 1-3. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD037381
Article and author information
Author details
Claudio De Virgilio
Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_166474/184671)
- Marco Caligaris
- Raffaele Nicastro
- Benjamin Pillet
- Claudio De Virgilio
Deutsche Forschungsgemeinschaft (RO 1028/5-2)
- Sabine Rospert
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_184781)
- Zehan Hu
- Jörn Dengjel
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (316030_177088)
- Zehan Hu
- Jörn Dengjel
Fonds Wetenschappelijk Onderzoek (G069413)
- Marie-Anne Deprez
- Joris Winderickx
Fonds Wetenschappelijk Onderzoek (G0C7222N)
- Marie-Anne Deprez
- Joris Winderickx
Katholieke Universiteit Leuven (C14/17/063)
- Marie-Anne Deprez
- Joris Winderickx
Katholieke Universiteit Leuven (C14/21/095)
- Marie-Anne Deprez
- Joris Winderickx
Ministero dell'Università e della Ricerca (2020-ATE-0329)
- Farida Tripodi
- Paola Coccetti
Deutsche Forschungsgemeinschaft (Project-ID 403222702 - SFB 1381,TP B08)
- Johannes Erwin Hummel
- Sabine Rospert
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Caligaris et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation
eLife 12:e84319.
https://doi.org/10.7554/eLife.84319
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