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

• Published in: Nature (London) 2017-02, Vol.542 (7641), p.357-361
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 631/45/275; 631/45/287/1182; Adaptor Proteins, Signal Transducing - deficiency; Adipocytes; Adipocytes - metabolism; Adipose tissue; Adiposity; Aging - metabolism; Amino acids; Amino Acyl-tRNA Synthetases - chemistry; Amino Acyl-tRNA Synthetases - genetics; Amino Acyl-tRNA Synthetases - metabolism; Aminoàcids; Animals; Body Weight; Cell Membrane - metabolism; Electron paramagnetic resonance; Fatty Acid Transport Proteins - metabolism; Fatty acids; Fatty Acids - chemistry; Fatty Acids - metabolism; Female; Fenotip; Humanities and Social Sciences; Insulin; Insulin - metabolism; Kinases; letter; Longevity - genetics; Male; Mechanistic Target of Rapamycin Complex 1; Metabolism; Metabolisme; Mice; Mice (Laboratory animals); multidisciplinary; Multiprotein Complexes - metabolism; Mutation; Obesitat; Obesity; Organ Size; Phenotype; Phosphorylation; Phosphoserine - metabolism; Protein Binding; Protein synthesis; Protein Transport; Ratolins (Animals de laboratori); Regulatory-Associated Protein of mTOR; Ressonància paramagnètica electrònica; Ribonucleic acid; Ribosomal Protein S6 Kinases, 90-kDa - deficiency; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; RNA; Rodents; Science; TOR Serine-Threonine Kinases - metabolism; Translocation
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature21380

Glutamyl-prolyl tRNA synthetase (EPRS) is a downstream effector of the mTORC1–S6K1 signalling axis and contributes to adiposity and ageing in mice. EPRS affects adiposity and ageing Mammalian target of rapamycin complex 1 (mTORC1) and p70 ribosomal protein S6 kinase 1 (S6K1) activate pathways that contribute to adipodicity and ageing. However, known mTORC1–S6K1 targets do not account for observed loss-of-function phenotypes, so there are likely to be additional downstream effectors. Here Paul Fox and colleagues show that glutamyl-prolyl-tRNA synthetase (EPRS) is an effector that contributes to adiposity and ageing. EPRS is phosphorylated by mTORC1–S6K1. Mice with phospho-deficient EPRS knocked in have low body weight, reduced adipose tissue mass, and increased lifespan, similar to S6K1-deficient mice or mice with adipocyte-specific deletion of raptor, a component of the mTORC1 complex. EPRS with a phospho-mimetic mutation rescue the body weight and adipodicity of S6K1-deficient mice, showing that EPRS phosphorylation mediates S6K1-dependent metabolic responses. In adipocytes, EPRS phosphorylation seems to be regulated by insulin. Phospho-EPRS interacts with fatty acid transport protein 1 (FATP1), resulting in FATP1 translocation to the plasma membrane and long-chain fatty acid uptake, which may at least partly explain the metabolic phenotype. 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 1 , 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 pathway 4 , 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 synthesis 7 , 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 mice 9 , 10 , 11 and mice with adipocyte-specific deficiency of raptor, an mTORC1 constituent 12 . Substitution