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Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation

Nature volume 637, pages E11–E14 (2025)Cite this article

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Matters Arising to this article was published on 08 January 2025

The Original Article was published on 16 May 2018

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arising from: Chen, J. et al. Nature https://doi.org/10.1038/s41586-018-0128-9 (2018).

Activation of the mechanistic target of rapamycin complex 1 (mTORC1) requires its nutrient-dependent recruitment to the surface of the lysosome, a process that is controlled by several multiprotein complexes, including GATOR1, a negative regulator of mTORC1 signalling1. Recently, Chen et al.2 suggested that KLHL22-dependent ubiquitylation and proteasomal degradation of the GATOR1 component DEPDC5 mediates mTORC1 activation by amino acids2. Here we report that the antibody central to the conclusions of Chen et al.2 neither sensitively nor specifically detects endogenous DEPDC5, and we determine, using validated antibodies and endogenously tagged cell lines, that the stability of DEPDC5 is insensitive to amino acid availability, proteasome activity and KLHL22 loss of function. These results call into question the conclusions of Chen et al.2 and indicate that alternative mechanisms convey nutrient availability to mTORC1.

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Fig. 1: Neither amino acid availability nor KLHL22 regulate DEPDC5 protein levels.

Data availability

The data supporting the findings of this study are available from the corresponding authors and the Whitehead Institute (sabadmin@wi.mit.edu) on request.

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Acknowledgements

We thank all of the members of the Sabatini and Chivukula Laboratories for insights. This work was supported by grants to D.M.S. from the NIH (R01 CA103866, R01 CA129105 and R01 AI47389), the Department of Defense (W81XWH-21-1-0260 and TS200035), the Lustgarten Foundation, the Leo Foundation, the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Pershing Square Philanthropies, fellowship support to M.L.V. (T32 GM007753, F30 CA228229, Koch Institute for Integrative Cancer Research at MIT), fellowship support to J.F.K. (T32 GM007753, F30 CA236179), support from the NIH to M.S.T. (T32CA009216, 1K08DK129824) and grants to R.R.C. (Burroughs Wellcome Fund, Ellison Foundation, Smith Family Foundation).

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Author notes

  1. These authors contributed equally: Max L. Valenstein, Pranav V. Lalgudi

Authors and Affiliations

  1. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Max L. Valenstein & Raghu R. Chivukula

  2. Whitehead Institute for Biomedical Research, Cambridge, MA, USA

    Max L. Valenstein, Pranav V. Lalgudi, Jibril F. Kedir, Kendall J. Condon, Anna Platzek & Daniel G. Freund

  3. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA

    Max L. Valenstein, Pranav V. Lalgudi, Jibril F. Kedir & Kendall J. Condon

  4. Harvard Medical School, Boston, MA, USA

    Max L. Valenstein, Martin S. Taylor & Raghu R. Chivukula

  5. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Martin S. Taylor

  6. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Yunhan Xu & Raghu R. Chivukula

  7. Department of Surgery, Massachusetts General Hospital, Boston, MA, USA

    Raghu R. Chivukula

  8. Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic

    David M. Sabatini

Authors
  1. Max L. Valenstein
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Contributions

M.L.V., P.V.L. and D.M.S. formulated the research plan. J.F.K., K.J.C., A.P., D.G.F. and M.S.T. generated endogenously tagged cell lines. M.L.V. generated KLHL22-knockout cells with assistance from Y.X. and R.R.C. M.L.V. and P.V.L. performed the experiments and interpreted results. M.L.V. wrote the manuscript. All of the authors reviewed and edited the manuscript.

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Correspondence to Max L. Valenstein.

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Competing interests

D.M.S. is a shareholder of Navitor Pharmaceuticals, which is targeting for therapeutic benefit the amino-acid-sensing pathway upstream of mTORC1.

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Valenstein, M.L., Lalgudi, P.V., Kedir, J.F. et al. Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation. Nature 637, E11–E14 (2025). https://doi.org/10.1038/s41586-024-07974-0

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