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mTORC1 activates SREBP-2 by suppressing cholesterol trafficking to lysosomes in mammalian cells

Walaa Eid1,2, Kristin Dauner3, Kevin C Courtney1

  • 1Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8L6.

Proceedings of the National Academy of Sciences of the United States of America
|July 12, 2017
PubMed

Insights

Mammalian target of rapamycin complex 1 (mTORC1) activates SREBP-2, a cholesterol synthesis regulator, by suppressing autophagy and endosomal recycling. This mechanism lowers ER cholesterol, thereby activating SREBP-2.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cholesterol homeostasis

Background:

  • Mammalian target of rapamycin complex 1 (mTORC1) activates sterol regulatory element-binding proteins (SREBPs), key regulators of cholesterol synthesis.
  • Activated SREBP-2 translocates to the nucleus to promote cholesterol synthesis gene expression.
  • Low endoplasmic reticulum (ER) cholesterol is a known trigger for SREBP-2 activation.

Purpose of the Study:

  • To investigate the mechanism by which mTORC1 activates SREBP-2, specifically examining its role in cholesterol delivery to the ER.
  • To determine if mTORC1 influences SREBP-2 activation by modulating cholesterol transport pathways.

Main Methods:

  • Investigated the relationship between mTORC1 activity, ER cholesterol levels, and SREBP-2 activation.
  • Utilized pharmacological inhibitors (U18666A) and genetic manipulation (NPC1 siRNA, Atg5-/-, dominant-negative rab5, Atg7 overexpression) to disrupt lysosomal cholesterol export and membrane trafficking pathways.
  • Assessed the impact of these manipulations on ER cholesterol levels and SREBP-2 activation.

Main Results:

  • mTORC1 activation correlated with decreased ER cholesterol and increased SREBP-2 activation.
  • Inhibition of cholesterol exit from lysosomes led to SREBP-2 activation independently of mTORC1.
  • Blocking autophagy and endosomal recycling to lysosomes caused SREBP-2 activation when mTORC1 activity was low.
  • Forced autophagy elevated ER cholesterol and suppressed SREBP-2 activation, even with high mTORC1 activity.

Conclusions:

  • mTORC1 suppresses autophagy and promotes endosomal recycling, preventing cholesterol-laden endosomes and autophagosomes from reaching lysosomes.
  • This suppression of lysosomal cholesterol delivery leads to reduced ER cholesterol levels.
  • The resulting low ER cholesterol activates SREBP-2, thereby promoting cholesterol synthesis.
Keywords:
SREBP-2autophagycholesterolendosomal recyclingmTORC1

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