Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release: evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase-3

J Biol Chem. 2007 Oct 26;282(43):31289-301. doi: 10.1074/jbc.M702777200. Epub 2007 Sep 6.


Most heat shock proteins (HSPs) have pro-survival functions. However, the role of HSP60, a mitochondrial matrix protein, is somewhat controversial with both pro-survival and pro-apoptotic functions reported. Here we show that in numerous apoptotic systems HSP60 protein accumulates in the cytosol. In BMD188-induced cell death, HSP60 accumulates in the cytosol with significant mitochondrial release. In contrast, in apoptosis induced by multiple other inducers, the cytosolic HSP60 accumulates without an apparent mitochondrial release. The short interfering RNA-mediated knockdown experiments revealed that in BMD188-induced apoptosis, HSP60 has a pro-death function and that the pro-death role of HSP60 seems to involve caspase-3 maturation and activation in the cytosol. In contrast, HSP60 appears to play a pro-survival role in other apoptotic systems where there is no apparent mitochondrial release as its knockdown promotes cell death. In these latter apoptotic systems HSP60 does not associate with active caspase-3. In both cases, HSP60 does not appreciably interact with Bax. Taken together, our results suggest the following: 1) cytosolic accumulation of HSP60 represents a common phenomenon during apoptosis induction; 2) cytosolic HSP60 accumulation during apoptosis occurs either with or without apparent mitochondrial release; and 3) the cytosolically accumulated HSP60 possesses either pro-survival or pro-death functions, which involves differential interactions with caspase-3.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Apoptosis*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Caspase 3 / metabolism*
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cells, Cultured
  • Chaperonin 60 / biosynthesis*
  • Chaperonin 60 / genetics
  • Cytosol / metabolism*
  • Down-Regulation / drug effects
  • Enzyme Activation / drug effects
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fluorescent Dyes
  • HCT116 Cells
  • Humans
  • Hydroxamic Acids / pharmacology
  • Indoles
  • Male
  • Mitochondria / metabolism*
  • Piperidones / pharmacology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Recombinant Proteins / metabolism
  • Subcellular Fractions / metabolism
  • Time Factors
  • Transfection


  • 1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one
  • Chaperonin 60
  • Fluorescent Dyes
  • Hydroxamic Acids
  • Indoles
  • Piperidones
  • RNA, Messenger
  • RNA, Small Interfering
  • Recombinant Proteins
  • DAPI
  • Caspase 3