Chaperone-mediated autophagy prevents apoptosis by degrading BBC3/PUMA

Autophagy. 2015;11(9):1623-35. doi: 10.1080/15548627.2015.1075688.


Autophagy is a potentially inimical pathway and together with apoptosis, may be activated by similar stress stimuli that can lead to cell death. The molecular cues that dictate the cell fate choice between autophagy and apoptosis remain largely unknown. Here we report that the proapoptotic protein BBC3/PUMA (BCL2 binding component 3) is a bona fide substrate of chaperone-mediated autophagy (CMA). BBC3 associates with HSPA8/HSC70 (heat shock 70kDa protein 8), leading to its lysosome translocation and uptake. Inhibition of CMA results in stabilization of BBC3, which in turn sensitizes tumor cells to undergo apoptosis. We further demonstrate that upon TNF (tumor necrosis factor) treatment, IKBKB/IKKβ (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase β)-mediated BBC3 Ser10 phosphorylation is crucial for BBC3 stabilization via blocking its degradation by CMA. Mechanistically, Ser10 phosphorylation facilitates BBC3 translocation from the cytosol to mitochondria. BBC3 stabilization resulting from either Ser10 phosphorylation or CMA inhibition potentiates TNF-induced apoptotic cell death. Our findings thus reveal that the selective degradation of BBC3 underlies the prosurvival role of CMA and define a previously unappreciated proapoptotic role of IKBKB that acts through phosphorylation-mediated stabilization of BBC3, thereby promoting TNF-triggered apoptosis.

Keywords: BBC3; IKBKB; IKKβ; PUMA; TNF; apoptosis; chaperone-mediated autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism*
  • Apoptosis* / drug effects
  • Autophagy* / drug effects
  • Cell Line, Tumor
  • Humans
  • I-kappa B Kinase / metabolism
  • Models, Biological
  • Molecular Chaperones / metabolism*
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Protein Stability / drug effects
  • Proteolysis* / drug effects
  • Proto-Oncogene Proteins / metabolism*
  • Serine / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology


  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • Molecular Chaperones
  • Proto-Oncogene Proteins
  • Tumor Necrosis Factor-alpha
  • Phosphoserine
  • Serine
  • I-kappa B Kinase