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GATOR1 regulates nitrogenic cataplerotic reactions of the mitochondrial TCA cycle

Nature Chemical Biology volume 13, pages 11791186 (2017) | Download Citation

Abstract

The GATOR1 (SEACIT) complex consisting of Iml1–Npr2–Npr3 inhibits target of rapamycin complex 1 (TORC1) in response to amino acid insufficiency. In glucose medium, Saccharomyces cerevisiae mutants lacking the function of this complex grow poorly in the absence of amino acid supplementation, despite showing hallmarks of increased TORC1 signaling. Such mutants sense that they are amino acid replete and thus repress metabolic activities that are important for achieving this state. We found that npr2Δ mutants have defective mitochondrial tricarboxylic acid (TCA)-cycle activity and retrograde response. Supplementation with glutamine, and especially aspartate, which are nitrogen-containing forms of TCA-cycle intermediates, rescues growth of npr2Δ mutants. These amino acids are then consumed in biosynthetic pathways that require nitrogen to support proliferative metabolism. Our findings revealed that negative regulators of TORC1, such as GATOR1 (SEACIT), regulate the cataplerotic synthesis of these amino acids from the TCA cycle, in tune with the amino acid and nitrogen status of cells.

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Acknowledgements

This work was supported by grants from the NIH (R01GM094314), CPRIT (RP140655), and the Welch Foundation (I-1797 to B.P.T.). We thank Y.-S. Yang for assistance with illustrations.

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Affiliations

  1. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Jun Chen
    • , Benjamin M Sutter
    • , Lei Shi
    •  & Benjamin P Tu

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Contributions

J.C., L.S., B.M.S., and B.P.T. conceived and designed the study. J.C., B.M.S., and L.S. conducted the experiments. L.S. first observed the ability of aspartate to rescue growth of GATOR1 (SEACIT) mutants. J.C. and B.P.T. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Benjamin P Tu.

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DOI

https://doi.org/10.1038/nchembio.2478