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http://hdl.handle.net/2445/129777
Title: | EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice |
Author: | 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. |
Keywords: | Aminoàcids Metabolisme Obesitat Fenotip Ressonància paramagnètica electrònica Ratolins (Animals de laboratori) Amino acids Metabolism Obesity Phenotype Electron paramagnetic resonance Mice (Laboratory animals) |
Issue Date: | 16-Feb-2017 |
Publisher: | Nature Publishing Group |
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 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), 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. |
Note: | Versió postprint del document publicat a: https://doi.org/10.1038/nature21380 |
It is part of: | Nature, 2017, vol. 542, num. 7641, p. 357-361 |
URI: | http://hdl.handle.net/2445/129777 |
Related resource: | https://doi.org/10.1038/nature21380 |
ISSN: | 0028-0836 |
Appears in Collections: | Articles publicats en revistes (Ciències Fisiològiques) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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