2. Academic Validation
  3. PTEN is both an activator and a substrate of chaperone-mediated autophagy

PTEN is both an activator and a substrate of chaperone-mediated autophagy

  • J Cell Biol. 2023 Sep 4;222(9):e202208150. doi: 10.1083/jcb.202208150.
Katherine K Zhang 1,  Calvin M Burns 2,  Mary E Skinner 3,  David B Lombard 4,  Richard A Miller 2 5,  S Joseph Endicott 2
Affiliations

Affiliations

  • 1 College of Literature, Arts, and the Sciences, University of Michigan, Ann Arbor , Ann Arbor, MI, USA.
  • 2 Department of Pathology, University of Michigan, Ann Arbor, Ann Arbor, MI, USA.
  • 3 Department of Neurology, University of Michigan, Ann Arbor, Ann Arbor, MI, USA.
  • 4 Department of Pathology and Laboratory Medicine, and Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 5 Geriatrics Center, University of Michigan, Ann Arbor , Ann Arbor, MI, USA.
PMID: 37418003 DOI: 10.1083/jcb.202208150
Abstract

PTEN is a crucial negative regulator of the INS/PI3K/Akt pathway and is one of the most commonly mutated tumor suppressors in Cancer. Global overexpression (OE) of PTEN in mice shifts metabolism to favor Oxidative Phosphorylation over glycolysis, reduces fat mass, and extends the lifespan of both sexes. We demonstrate that PTEN regulates chaperone-mediated Autophagy (CMA). Using cultured cells and mouse models, we show that PTEN OE enhances CMA, dependent upon PTEN's lipid Phosphatase activity and Akt inactivation. Reciprocally, PTEN knockdown reduces CMA, which can be rescued by inhibiting class I PI3K or Akt. Both PTEN and CMA are negative regulators of glycolysis and lipid droplet formation. We show that suppression of glycolysis and lipid droplet formation downstream of PTEN OE depends on CMA activity. Finally, we show that PTEN protein levels are sensitive to CMA and that PTEN accumulates in lysosomes with elevated CMA. Collectively, these data suggest that CMA is both an effector and a regulator of PTEN.

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