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  1. 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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  2. 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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