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Nutrient signaling in protein homeostasis: an increase in quantity at the expense of quality

Crystal S Conn1, Shu-Bing Qian

  • 1Graduate Field of Genetics, Genomics and Development, Cornell University, Ithaca, NY 14853, USA.

Science Signaling
|April 18, 2013
PubMed

Insights

Rapamycin extends lifespan by improving protein quality, not just reducing synthesis. It slows ribosomal elongation, enhancing translation fidelity and organismal health.

Area of Science:

  • Molecular Biology
  • Aging Research
  • Cellular Metabolism

Background:

  • Rapamycin extends lifespan across species, prompting investigation into its molecular mechanisms.
  • Mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth and aging via mRNA translation.
  • The link between mTORC1 inhibition, reduced protein synthesis, and lifespan extension is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which mTORC1 inhibition by rapamycin extends lifespan.
  • To investigate the impact of mTORC1 signaling on protein synthesis quality and translation fidelity.
  • To identify downstream targets of mTORC1 involved in maintaining protein homeostasis.

Main Methods:

  • Utilized constitutively active mTORC1 signaling to assess effects on protein synthesis.
  • Analyzed translation fidelity and ribosomal elongation rates under varying mTORC1 activity.
  • Investigated the role of S6 kinases and 4E-BP proteins in rapamycin's effects on protein quality.

Main Results:

  • Constitutively active mTORC1 increased protein synthesis but decreased polypeptide quality by accelerating ribosomal elongation.
  • Rapamycin treatment restored protein quality by slowing ribosomal elongation, enhancing translation fidelity.
  • Loss of S6 kinases, but not 4E-BP proteins, mimicked some effects of rapamycin on protein quality.

Conclusions:

  • mTORC1 signaling directly impacts protein synthesis quality and translation fidelity.
  • Slowing ribosomal elongation is a key mechanism by which rapamycin improves protein quality and potentially extends lifespan.
  • Nutrient signaling through mTORC1 plays a central role in regulating growth and aging via protein homeostasis.

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