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

Metabolic pathways contributing to adiposity and aging are activated by the mammalian target of rapamycin complex 1 (mTORC1) and p70 ribosomal protein S6 kinase 1 (S6K1) axis(1–3). However, known mTORC1-S6K1 targets do not account for observed loss-of-function phenotypes, suggesting additional downstream effectors(4–6). Here we identify glutamyl-prolyl tRNA synthetase (EPRS) as an mTORC1-S6K1 target that contributes importantly to adiposity and aging. EPRS phosphorylation at Ser(999) by mTORC1-S6K1 induces its release from the aminoacyl tRNA multisynthetase complex (MSC), required for execution of noncanonical functions beyond protein synthesis(7,8). To investigate physiological function of EPRS phosphorylation, we generated EPRS knock-in mice bearing phospho-deficient Ser(999)-to-Ala (S999A) and phospho-mimetic (S999D) mutations. Homozygous S999A mice exhibited low body weight, reduced adipose tissue mass, and increased lifespan, thereby displaying notable similarities with S6K1-deficient mice(9–11) and mice with adipocyte-specific deficiency of raptor, an mTORC1 constituent(12). Substitution of the EPRS S999D allele in S6K1-deficient mice normalized body mass and adiposity, indicating EPRS phosphorylation mediates S6K1-dependent metabolic responses. In adipocytes, insulin stimulated S6K1-dependent EPRS phosphorylation and release from the MSC. Interaction screening revealed phospho-EPRS binds Slc27a1 (i.e., fatty acid transport protein 1, FATP1)(13–15), inducing its translocation to the plasma membrane and long-chain fatty acid uptake. Thus, EPRS and FATP1 are terminal mTORC1-S6K1 axis effectors critical for metabolic phenotypes.