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

Abul Arif, Fulvia Terenzi, Alka A. Potdar, Jie Jia, Jessica Sacks, Arnab China, Dalia Halawani, Kommireddy Vasu, Xiaoxia Li, J. Mark Brown, Jie Chen, Sara C. Kozma, George Thomas, Paul L. Fox

Research output: Contribution to journalArticle

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) axis. However, known mTORC1-S6K1 targets do not account for observed loss-of-function phenotypes, suggesting that there are additional downstream effectors of this pathway. 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 synthesis. 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 mice and mice with adipocyte-specific deficiency of raptor, an mTORC1 constituent. Substitution of the Eprs S999D 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), 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.

Original languageEnglish (US)
Pages (from-to)357-361
Number of pages5
JournalNature
Volume542
Issue number7641
DOIs
StatePublished - Feb 16 2017

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Ribosomal Protein S6 Kinases
Adiposity
Fatty Acid Transport Proteins
Phosphorylation
Adipocytes
Raptors
Phenotype
mechanistic target of rapamycin complex 1
Transfer RNA
Metabolic Networks and Pathways
Adipose Tissue
Fatty Acids
Alleles
Body Weight
Cell Membrane
Insulin

ASJC Scopus subject areas

  • General

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Arif, A., Terenzi, F., Potdar, A. A., Jia, J., Sacks, J., China, A., ... Fox, P. L. (2017). EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. Nature, 542(7641), 357-361. https://doi.org/10.1038/nature21380

EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. / Arif, Abul; Terenzi, Fulvia; Potdar, Alka A.; Jia, Jie; Sacks, Jessica; China, Arnab; Halawani, Dalia; Vasu, Kommireddy; Li, Xiaoxia; Brown, J. Mark; Chen, Jie; Kozma, Sara C.; Thomas, George; Fox, Paul L.

In: Nature, Vol. 542, No. 7641, 16.02.2017, p. 357-361.

Research output: Contribution to journalArticle

Arif, A, Terenzi, F, Potdar, AA, Jia, J, Sacks, J, China, A, Halawani, D, Vasu, K, Li, X, Brown, JM, Chen, J, Kozma, SC, Thomas, G & Fox, PL 2017, 'EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice', Nature, vol. 542, no. 7641, pp. 357-361. https://doi.org/10.1038/nature21380
Arif A, Terenzi F, Potdar AA, Jia J, Sacks J, China A et al. EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. Nature. 2017 Feb 16;542(7641):357-361. https://doi.org/10.1038/nature21380
Arif, Abul ; Terenzi, Fulvia ; Potdar, Alka A. ; Jia, Jie ; Sacks, Jessica ; China, Arnab ; Halawani, Dalia ; Vasu, Kommireddy ; Li, Xiaoxia ; Brown, J. Mark ; Chen, Jie ; Kozma, Sara C. ; Thomas, George ; Fox, Paul L. / EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. In: Nature. 2017 ; Vol. 542, No. 7641. pp. 357-361.
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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) axis. However, known mTORC1-S6K1 targets do not account for observed loss-of-function phenotypes, suggesting that there are additional downstream effectors of this pathway. 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 synthesis. 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 mice and mice with adipocyte-specific deficiency of raptor, an mTORC1 constituent. Substitution of the Eprs S999D 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), 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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AU - Arif, Abul

AU - Terenzi, Fulvia

AU - Potdar, Alka A.

AU - Jia, Jie

AU - Sacks, Jessica

AU - China, Arnab

AU - Halawani, Dalia

AU - Vasu, Kommireddy

AU - Li, Xiaoxia

AU - Brown, J. Mark

AU - Chen, Jie

AU - Kozma, Sara C.

AU - Thomas, George

AU - Fox, Paul L.

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