Letter | Published:

Coordinated regulation of protein synthesis and degradation by mTORC1

Nature volume 513, pages 440443 (18 September 2014) | Download Citation

Abstract

Eukaryotic cells coordinately control anabolic and catabolic processes to maintain cell and tissue homeostasis. Mechanistic target of rapamycin complex 1 (mTORC1) promotes nutrient-consuming anabolic processes, such as protein synthesis1. Here we show that as well as increasing protein synthesis, mTORC1 activation in mouse and human cells also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits. The increase in proteasome gene expression, cellular proteasome content, and rates of protein turnover downstream of mTORC1 were all dependent on induction of the transcription factor nuclear factor erythroid-derived 2-related factor 1 (NRF1; also known as NFE2L1). Genetic activation of mTORC1 through loss of the tuberous sclerosis complex tumour suppressors, TSC1 or TSC2, or physiological activation of mTORC1 in response to growth factors or feeding resulted in increased NRF1 expression in cells and tissues. We find that this NRF1-dependent elevation in proteasome levels serves to increase the intracellular pool of amino acids, which thereby influences rates of new protein synthesis. Therefore, mTORC1 signalling increases the efficiency of proteasome-mediated protein degradation for both quality control and as a mechanism to supply substrate for sustained protein synthesis.

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Acknowledgements

We thank I. Ben-Sahra and L. Yang for technical assistance. This work was supported in part by Department of Defense Tuberous Sclerosis Complex Research Program grant W81XWH-10-1-0861 (B.D.M.), National Institutes of Health grants CA122617 (B.D.M.) and CA120964 (B.D.M. and D.J.K.), the Ellison Medical Foundation (B.D.M.), National Science Foundation fellowship DGE-1144152 (S.J.H.R.), and a Canadian Institutes of Health Research fellowship (S.B.W.).

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Affiliations

  1. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA

    • Yinan Zhang
    • , Justin Nicholatos
    • , Stéphane J. H. Ricoult
    • , Scott B. Widenmaier
    • , Gökhan S. Hotamisligil
    •  & Brendan D. Manning
  2. Translational Medicine Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • John R. Dreier
    •  & David J. Kwiatkowski

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Contributions

B.D.M. and Y.Z. designed and interpreted the experiments and wrote the manuscript. Y.Z., J.N., J.R.D., S.J.H.R. and S.B.W. performed the experiments. G.S.H. and D.J.K. provided key materials and technical guidance.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Brendan D. Manning.

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https://doi.org/10.1038/nature13492

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