Nutrient control of growth and metabolism through mTORC1 regulation of mRNA splicing

Cellular growth and organismal development are remarkably complex processes that require the nutrient-responsive kinase mechanistic target of rapamycin complex 1 (mTORC1). Anticipating that important mTORC1 functions remained to be identified, we employed genetic and bioinformatic screening in C. elegans to uncover mechanisms of mTORC1 action. Here, we show that during larval growth, nutrients induce an extensive reprogramming of gene expression and alternative mRNA splicing by acting through mTORC1. mTORC1 regulates mRNA splicing and the production of protein-coding mRNA isoforms largely independently of its target p70 S6 kinase (S6K) by increasing the activity of the serine/arginine-rich (SR) protein RSP-6 (SRSF3/7) and other splicing factors. mTORC1-mediated mRNA splicing regulation is critical for growth; mediates nutrient control of mechanisms that include energy, nucleotide, amino acid, and other metabolic pathways; and may be conserved in humans. Although mTORC1 inhibition delays aging, mTORC1-induced mRNA splicing promotes longevity, suggesting that when mTORC1 is inhibited, enhancement of this splicing might provide additional anti-aging benefits. [Display omitted] •During C. elegans growth, mTORC1 broadly controls mRNA splicing and expression•mTORC1 increases the expression and activity of SR proteins and other splicing factors•mTORC1 controls growth-related metabolic pathways by regulating mRNA splicing•Regulating metabolic genes through mRNA splicing is a conserved mTORC1 function Ogawa et al. show in Caenorhabditis elegans that the essential growth regulator mTORC1 extensively reprograms gene expression and alternative mRNA splicing. This splicing regulation is critical for growth, orchestrates growth-associated metabolism, and appears to be conserved. Maintaining mTORC1-induced splicing may be beneficial for longevity under conditions of mTORC1 inhibition.