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

Takafumi Ogawa; Meltem Isik; Ziyun Wu; Kiran Kurmi; Jin Meng; Sungyun Cho; Gina Lee; L Paulette Fernandez-Cardenas; Masaki Mizunuma; John Blenis; Marcia C Haigis; T Keith Blackwell

doi:10.1016/j.molcel.2024.10.037

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

Mol Cell. 2024 Nov 15:S1097-2765(24)00877-3. doi: 10.1016/j.molcel.2024.10.037. Online ahead of print.

Authors

Affiliations

¹ Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Unit of Biotechnology, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan; Hiroshima Research Center for Healthy Aging (HiHA), Hiroshima University, Higashi-Hiroshima, Japan.
² Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
³ Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China.
⁴ Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center, Harvard Medical School, Boston, MA 02115, USA.
⁵ Meyer Cancer Center and Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA.
⁶ Meyer Cancer Center and Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021, USA; Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA 92617, USA.
⁷ Unit of Biotechnology, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan; Hiroshima Research Center for Healthy Aging (HiHA), Hiroshima University, Higashi-Hiroshima, Japan.
⁸ Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: keith.blackwell@joslin.harvard.edu.

PMID: 39571580
DOI: 10.1016/j.molcel.2024.10.037

Abstract

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.

Keywords: C. elegans; SR proteins; development; gene expression; growth; human cell growth; longevity; mRNA splicing; mTORC1; metabolism; nutrient response.