Letter | Published:

EPRS is a critical mTORC1–S6K1 effector that influences adiposity in mice

Nature volume 542, pages 357361 (16 February 2017) | Download Citation

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Abstract

Metabolic pathways that contribute to adiposity and ageing are activated by the mammalian target of rapamycin complex 1 (mTORC1) and p70 ribosomal protein S6 kinase 1 (S6K1) axis1,2,3. However, known mTORC1–S6K1 targets do not account for observed loss-of-function phenotypes, suggesting that there are additional downstream effectors of this pathway4,5,6. Here we identify glutamyl-prolyl-tRNA synthetase (EPRS) as an mTORC1–S6K1 target that contributes to adiposity and ageing. Phosphorylation of EPRS at Ser999 by mTORC1–S6K1 induces its release from the aminoacyl tRNA multisynthetase complex, which is required for execution of noncanonical functions of EPRS beyond protein synthesis7,8. To investigate the physiological function of EPRS phosphorylation, we generated Eprs knock-in mice bearing phospho-deficient Ser999-to-Ala (S999A) and phospho-mimetic (S999D) mutations. Homozygous S999A mice exhibited low body weight, reduced adipose tissue mass, and increased lifespan, similar to S6K1-deficient mice9,10,11 and mice with adipocyte-specific deficiency of raptor, an mTORC1 constituent12. Substitution of the EprsS999D allele in S6K1-deficient mice normalized body mass and adiposity, indicating that EPRS phosphorylation mediates S6K1-dependent metabolic responses. In adipocytes, insulin stimulated S6K1-dependent EPRS phosphorylation and release from the multisynthetase complex. Interaction screening revealed that phospho-EPRS binds SLC27A1 (that is, fatty acid transport protein 1, FATP1)13,14,15, inducing its translocation to the plasma membrane and long-chain fatty acid uptake. Thus, EPRS and FATP1 are terminal mTORC1–S6K1 axis effectors that are critical for metabolic phenotypes.

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Acknowledgements

This work was supported by NIH grants P01HL029582, P01HL076491, R01GM086430, R01GM115476, and P50CA150964 (to P.L.F.), by AHA SDG 10SDG3930003 (to A.A), by CIHR fellowship (to D.H), by AHA fellowship (to K.V.), by NIH R01AR048914 and R01GM089771 (to J.C.), by Spanish Ministry BFU2012-38867 and Fundacio La Marato de TV3 #174/U/2016 grants (to S.C.K.), and by NIH R01CA158768, Spanish Ministry SAF2011-24967, and CIG European Commission PCIG10-GA-2011-304160 grants (to G.T.). We thank P. Bhattaram for helpful discussion.

Author information

Affiliations

  1. Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA

    • Abul Arif
    • , Fulvia Terenzi
    • , Jie Jia
    • , Jessica Sacks
    • , Arnab China
    • , Dalia Halawani
    • , Kommireddy Vasu
    • , J. Mark Brown
    •  & Paul L. Fox
  2. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA

    • Alka A. Potdar
  3. Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA

    • Xiaoxia Li
  4. Department of Cell and Developmental Biology, University of Illinois, Urbana, Illinois 61801, USA

    • Jie Chen
  5. Catalan Institute of Oncology, ICO, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain

    • Sara C. Kozma
    •  & George Thomas
  6. Department of Physiological Sciences II, Faculty of Medicine, University of Barcelona, 08908 Barcelona, Spain

    • Sara C. Kozma
    •  & George Thomas
  7. Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA

    • George Thomas

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Contributions

A.A. and P.L.F. conceived and interpreted most experiments with contributions from J.M.B., J.C., S.C.K., G.T. and X.L. A.A. performed most experiments with contributions from J.J., F.T., J.S., A.C., D.H. and K.V. A.A.P. performed longevity analysis. A.A. and P.L.F. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paul L. Fox.

Reviewer Information Nature thanks A. Stahl and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature21380

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