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

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. · pubmed

Paper

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.

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Research summary

The paper explores the role of mTORC1 in regulating mRNA splicing and its implications for growth and metabolism, which are critical processes in the context of aging. The findings suggest that mTORC1's regulation of splicing could have a role in longevity, particularly in the context of nutrient signaling and aging. However, while the research presents solid findings, it does not introduce a major breakthrough or transformative insights that would significantly advance the field of longevity research. Thus, it is rated as a solid contribution with limited impact.

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