Manganese is a physiologically relevant TORC1 activator in yeast and mammals
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Evaluation Summary:
Nicastro et al. uncover a new input for the central metabolic regulator TOR complex 1 (TORC1) , namely manganese (Mn) levels, in budding yeast and they show that this dependence on Mn is conserved in humans. TORC1 is a central coordinator of multiple inputs to guide cellular decisions of catabolism vs anabolism, and information on an additional way to modulate its activity will be highly influential in both basic cell biology as well as therapeutic research.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1
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Abstract
The essential biometal manganese (Mn) serves as a cofactor for several enzymes that are crucial for the prevention of human diseases. Whether intracellular Mn levels may be sensed and modulate intracellular signaling events has so far remained largely unexplored. The highly conserved target of rapamycin complex 1 (TORC1, mTORC1 in mammals) protein kinase requires divalent metal cofactors such as magnesium (Mg 2+ ) to phosphorylate effectors as part of a homeostatic process that coordinates cell growth and metabolism with nutrient and/or growth factor availability. Here, our genetic approaches reveal that TORC1 activity is stimulated in vivo by elevated cytoplasmic Mn levels, which can be induced by loss of the Golgi-resident Mn 2+ transporter Pmr1 and which depend on the natural resistance-associated macrophage protein (NRAMP) metal ion transporters Smf1 and Smf2. Accordingly, genetic interventions that increase cytoplasmic Mn 2+ levels antagonize the effects of rapamycin in triggering autophagy, mitophagy, and Rtg1-Rtg3-dependent mitochondrion-to-nucleus retrograde signaling. Surprisingly, our in vitro protein kinase assays uncovered that Mn 2+ activates TORC1 substantially better than Mg 2+ , which is primarily due to its ability to lower the K m for ATP, thereby allowing more efficient ATP coordination in the catalytic cleft of TORC1. These findings, therefore, provide both a mechanism to explain our genetic observations in yeast and a rationale for how fluctuations in trace amounts of Mn can become physiologically relevant. Supporting this notion, TORC1 is also wired to feedback control mechanisms that impinge on Smf1 and Smf2. Finally, we also show that Mn 2+ -mediated control of TORC1 is evolutionarily conserved in mammals, which may prove relevant for our understanding of the role of Mn in human diseases.
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Evaluation Summary:
Nicastro et al. uncover a new input for the central metabolic regulator TOR complex 1 (TORC1) , namely manganese (Mn) levels, in budding yeast and they show that this dependence on Mn is conserved in humans. TORC1 is a central coordinator of multiple inputs to guide cellular decisions of catabolism vs anabolism, and information on an additional way to modulate its activity will be highly influential in both basic cell biology as well as therapeutic research.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1
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Public Review:
This manuscript uses budding yeast to uncover a new input for the central metabolic regulator TOR complex 1 (TORC1): manganese (Mn) levels. Using both genetic manipulations in vivo, as well as in vitro protein kinase assays, they show that Mn levels are direct inducers of TORC1 activity and that TORC1 activity modulates intracellular Mn levels. Importantly, they show that this dependence on Mn is conserved to humans. The combination of both in vivo and in vitro approaches as well as the demonstration of conservation of this phenomenon make the manuscript both broad and deep. While the authors do not actually measure intracellular levels of Mn at any point, they do bring a plethora of indirect evidence that Mn levels are indeed the defining parameter for TORC1 in vivo, and this is corroborated by the in vitro studies.
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