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Cholesterol regulates insulin-induced mTORC1 signaling

Kolaparamba V Navyasree1,2, Shikha T Ramesh1,2, Perunthottathu K Umasankar1

  • 1Intracellular Trafficking Laboratory, Transdisciplinary Biology Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala 695014, India.

Journal of Cell Science
|November 3, 2023
PubMed

Insights

Cholesterol is crucial for insulin-stimulated mechanistic target of rapamycin complex-1 (mTORC1) signaling, essential for cell growth. This study reveals cholesterol

Area of Science:

  • Cellular signaling and metabolism
  • Molecular mechanisms of growth regulation

Background:

  • Insulin-stimulated mechanistic target of rapamycin complex-1 (mTORC1) signaling is vital for mammalian cell growth.
  • The precise regulatory factors governing insulin-induced mTORC1 activation remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of cholesterol in regulating insulin-stimulated mTORC1 signaling.
  • To investigate how cholesterol influences mTORC1 localization and activation.
  • To explore cholesterol's role in mTORC1 reactivation during starvation and its implications in Smith-Lemli-Opitz Syndrome (SLOS).

Main Methods:

  • Depletion and repletion of cellular cholesterol.
  • Analysis of mTORC1 recruitment to lysosomes and TSC complex dissociation.
  • Investigation of cholesterol's interaction with autophagy for mTORC1 reactivation.
  • Assessment of insulin-mTORC1 signaling in SLOS fibroblasts and HeLa-SLOS cells.

Main Results:

  • Insulin-induced mTORC1 signaling is impaired in cholesterol-depleted cells and restored upon cholesterol repletion.
  • Cholesterol facilitates mTORC1 recruitment to lysosomes, promoting complete activation without altering TSC complex dynamics.
  • Cholesterol collaborates with autophagy to enable mTORC1 reactivation under starvation, rescuing insulin responsiveness.
  • SLOS cells, deficient in cholesterol biosynthesis, exhibit defective insulin-mTORC1 signaling, which is rescued by cholesterol supplementation or activated Rag GTPase.

Conclusions:

  • Cholesterol is a critical regulator of insulin-stimulated mTORC1 signaling, essential for cell growth.
  • Cholesterol orchestrates the spatial and temporal control of mTORC1 activation through lysosomal recruitment.
  • Defects in cholesterol biosynthesis lead to impaired mTORC1 signaling, highlighting cholesterol's importance in growth regulation and disease.
Keywords:
CholesterolInsulinLysosomeSignalingmTORC1

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