Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis

Nat Cell Biol. 2015 Jun;17(6):759-70. doi: 10.1038/ncb3166. Epub 2015 May 11.


Chaperone-mediated autophagy (CMA) selectively degrades a subset of cytosolic proteins in lysosomes. A potent physiological activator of CMA is nutrient deprivation, a condition in which intracellular triglyceride stores or lipid droplets (LDs) also undergo hydrolysis (lipolysis) to generate free fatty acids for energetic purposes. Here we report that the LD-associated proteins perilipin 2 (PLIN2) and perilipin 3 (PLIN3) are CMA substrates and their degradation through CMA precedes lipolysis. In vivo studies revealed that CMA degradation of PLIN2 and PLIN3 was enhanced during starvation, concurrent with elevated levels of cytosolic adipose triglyceride lipase (ATGL) and macroautophagy proteins on LDs. CMA blockage both in cultured cells and mouse liver or expression of CMA-resistant PLINs leads to reduced association of ATGL and macrolipophagy-related proteins with LDs and the subsequent decrease in lipid oxidation and accumulation of LDs. We propose a role for CMA in LD biology and in the maintenance of lipid homeostasis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3 Cells
  • Animals
  • Autophagy*
  • Carrier Proteins / metabolism
  • Cell Line
  • Fatty Acids / metabolism
  • Fatty Liver / genetics
  • HSC70 Heat-Shock Proteins / metabolism
  • Lipase / metabolism
  • Lipid Droplets / metabolism*
  • Lipid Metabolism
  • Lipolysis*
  • Liver / metabolism*
  • Lysosomal-Associated Membrane Protein 2 / genetics
  • Lysosomes / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Chaperones / metabolism*
  • Oxidation-Reduction
  • Perilipin-2
  • Perilipin-3
  • Protein Binding
  • Rats
  • Rats, Wistar
  • Starvation / metabolism


  • Carrier Proteins
  • Fatty Acids
  • HSC70 Heat-Shock Proteins
  • Hspa8 protein, mouse
  • Lysosomal-Associated Membrane Protein 2
  • Membrane Proteins
  • Molecular Chaperones
  • Perilipin-2
  • Perilipin-3
  • Plin2 protein, mouse
  • Plin2 protein, rat
  • Plin3 protein, mouse
  • Lipase
  • PNPLA2 protein, mouse