Single-nucleotide polymorphisms in the first intron of the gene encoding FTO (fat mass and obesity associated), which can demethylate various nucleic acids in vitro, are associated with increased body mass index in humans. Mice deficient in FTO show severe growth retardation, leading Gulati et al. to investigate the molecular basis for this phenotype. The rates of proliferation and mRNA translation were lower in Fto–/– mouse embryonic fibroblasts (MEFs) than in wild-type MEFs. mRNA translation requires the multitransfer RNA (tRNA) synthetase complex (MSC), and the abundance of protein and mRNA components in the MSC was lower in Fto–/– MEFs than in wild-type MEFs. The mammalian target of rapamycin complex (mTORC1) promotes cellular growth and proliferation when nutrients such as amino acids are available, and leucyl tRNA synthase acts as an amino acid sensor for mTORC1. Fto–/– MEFs showed decreased viability in response to amino acid depletion, reduced basal mTORC1 signaling, and decreased abundance of leucyl tRNA synthetase. Amino acid deprivation failed to reduce mTORC1 signaling in HEK 293 cells overexpressing FTO but not in cells overexpressing a catalytically inactive form of FTO. Proteomic analysis revealed that tagged FTO interacted with methionyl, tyrosyl, arginyl, and phenylalanyl tRNA synthetases, and coimmunoprecipitation experiments suggested that FTO interacted with methionyl tRNA synthetase that was not part of the MSC. Thus, FTO appears to contribute to the ability of mTORC1 to respond to amino acid availability and may help to explain the stunted growth of individuals who are homozygous for a catalytically inactive form of FTO. However, it is unclear how the demethylation activity of FTO is involved in amino acid sensing by mTORC1.
P. Gulati, M. K. Cheung, R. Antrobus, C. D. Church, H. P. Harding, Y.-C. L. Tung, D. Rimmington, M. Ma, D. Ron, P. J. Lehner, F. M. Ashcroft, R. D. Cox, A. P. Coll, S. O’Rahilly, G. S. H. Yeo, Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc. Natl. Acad. Sci. U.S.A. 110, 2557–2562 (2013). [Abstract] [Full Text]