TY - JOUR
T1 - GATOR1 regulates nitrogenic cataplerotic reactions of the mitochondrial TCA cycle
AU - Chen, Jun
AU - Sutter, Benjamin M.
AU - Shi, Lei
AU - Tu, Benjamin P.
N1 - Funding Information:
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.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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 npr2 " 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 npr2 " 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.
AB - 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 npr2 " 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 npr2 " 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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U2 - 10.1038/nchembio.2478
DO - 10.1038/nchembio.2478
M3 - Article
C2 - 28920930
AN - SCOPUS:85031780277
SN - 1552-4450
VL - 13
SP - 1179
EP - 1186
JO - Nature chemical biology
JF - Nature chemical biology
IS - 11
ER -