Letter | Published:

Coordinated regulation of protein synthesis and degradation by mTORC1

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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nature Cell Biol. 15, 555–564 (2013)

  2. 2.

    , & mTOR in aging, metabolism, and cancer. Curr. Opin. Genet. Dev. 23, 53–62 (2013)

  3. 3.

    , , & Failure of amino acid homeostasis causes cell death following proteasome inhibition. Mol. Cell 48, 242–253 (2012)

  4. 4.

    , , , & A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP. Neuron 52, 239–245 (2006)

  5. 5.

    & Autophagy in the cellular energetic balance. Cell Metab. 13, 495–504 (2011)

  6. 6.

    et al. Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab. 8, 325–332 (2008)

  7. 7.

    et al. Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol. Cell 38, 17–28 (2010)

  8. 8.

    , , & Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. Mol. Cell 40, 147–158 (2010)

  9. 9.

    et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010)

  10. 10.

    , & p97-dependent retrotranslocation and proteolytic processing govern formation of active Nrf1 upon proteasome inhibition. eLife 3, e01856 (2014)

  11. 11.

    et al. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 29, 541–551 (2008)

  12. 12.

    & The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739–789 (2005)

  13. 13.

    et al. Microarray analyses of SREBP-1a and SREBP-1c target genes identify new regulatory pathways in muscle. Physiol. Genomics 34, 327–337 (2008)

  14. 14.

    , , , & Genome-wide occupancy of SREBP1 and its partners NFY and SP1 reveals novel functional roles and combinatorial regulation of distinct classes of genes. PLoS Genet. 4, e1000133 (2008)

  15. 15.

    et al. Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features. Hum. Mol. Genet. 21, 4286–4300 (2012)

  16. 16.

    , & Nuclear factor-erythroid 2-related factor 1 regulates expression of proteasome genes in hepatocytes and protects against endoplasmic reticulum stress and steatosis in mice. FEBS J. 280, 3609–3620 (2013)

  17. 17.

    et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab. 14, 21–32 (2011)

  18. 18.

    , , , & Selective coactivator interactions in gene activation by SREBP-1a and -1c. Mol. Cell. Biol. 24, 8288–8300 (2004)

  19. 19.

    et al. A simplified system for generating recombinant adenoviruses. Proc. Natl Acad. Sci. USA 95, 2509–2514 (1998)

  20. 20.

    , , & The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol. Cell. Biol. 28, 4104–4115 (2008)

  21. 21.

    et al. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet. 11, 525–534 (2002)

  22. 22.

    et al. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J. Clin. Invest. 112, 1223–1233 (2003)

  23. 23.

    , , & Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 361, 1348–1349 (2003)

  24. 24.

    et al. Biopython: freely available Python tools for computational molecular biology and bioinformatics. Bioinformatics 25, 1422–1423 (2009)

  25. 25.

    , & Sterols regulate 3β-hydroxysterol Δ24-reductase (DHCR24) via dual sterol regulatory elements: cooperative induction of key enzymes in lipid synthesis by sterol regulatory element binding proteins. Biochim. Biophys. Acta 1821, 1350–1360 (2012)

  26. 26.

    , , & WebLogo: a sequence logo generator. Genome Res. 14, 1188–1190 (2004)

  27. 27.

    et al. Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947–2948 (2007)

Download references


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.).

Author information


  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


  1. Search for Yinan Zhang in:

  2. Search for Justin Nicholatos in:

  3. Search for John R. Dreier in:

  4. Search for Stéphane J. H. Ricoult in:

  5. Search for Scott B. Widenmaier in:

  6. Search for Gökhan S. Hotamisligil in:

  7. Search for David J. Kwiatkowski in:

  8. Search for Brendan D. Manning in:


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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Brendan D. Manning.

Extended data

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.