Effects of small molecules on chaperone-mediated autophagy

Autophagy. 2005 Oct-Dec;1(3):141-5. doi: 10.4161/auto.1.3.2000. Epub 2005 Oct 11.

Abstract

Autophagy, including macroautophagy (MA), chaperone-mediated autophagy (CMA), crinophagy, pexophagy and microautophagy, are processes by which cells select internal components such as proteins, secretory vesicles, organelles, or foreign bodies, and deliver them to lysosomes for degradation. MA and CMA are activated during conditions of serum withdrawal in cell culture and during short-term and prolonged starvation in organisms, respectively. Although MA and CMA are activated under similar conditions, they are regulated by different mechanisms. We used pulse/chase analysis under conditions in which most intracellular proteolysis is due to CMA to test a variety of compounds for effects on this process. We show that inhibitors of MA such as 3-methyladenine, wortmannin, and LY294002 have no effect on CMA. Protein degradation by MA is sensitive to microtubule inhibitors such as colcemide and vinblastine, but protein degradation by CMA is not. Activators of MA such as rapamycin also have no effect on CMA. We demonstrate that CMA, like MA, is inhibited by protein synthesis inhibitors anisomycin and cycloheximide. CMA is also partially inhibited when the p38 mitogen activated protein kinase is blocked. Finally we demonstrate that the glucose-6-phophate dehydrogenase inhibitor, 6-aminonicotinamide, and heat shock protein of 90 kilodaltons inhibitor, geldanamycin, have the ability to activate CMA.

MeSH terms

  • 6-Aminonicotinamide / pharmacology
  • Autophagy / drug effects
  • Autophagy / physiology*
  • Benzoquinones / pharmacology
  • Cell Line
  • Fibroblasts / cytology
  • Glucosephosphate Dehydrogenase / antagonists & inhibitors
  • Glucosephosphate Dehydrogenase / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Lactams, Macrocyclic / pharmacology
  • Lysosomes / metabolism
  • Molecular Chaperones / physiology*
  • Protein Synthesis Inhibitors / pharmacology
  • Tubulin Modulators / pharmacology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Molecular Chaperones
  • Protein Synthesis Inhibitors
  • Tubulin Modulators
  • 6-Aminonicotinamide
  • Glucosephosphate Dehydrogenase
  • p38 Mitogen-Activated Protein Kinases
  • geldanamycin