The anti-apoptotic function of human αA-crystallin is directly related to its chaperone activity

Cell Death Dis. 2010;1(3):e31. doi: 10.1038/cddis.2010.3.


αA-crystallin is a molecular chaperone and an antiapoptotic protein. This study investigated the mechanism of inhibition of apoptosis by human αA-crystallin and determined if the chaperone activity of αA-crystallin is required for the antiapoptotic function. αA-crystallin inhibited chemical-induced apoptosis in Chinese hamster ovary (CHO) cells and HeLa cells by inhibiting activation of caspase-3 and -9. In CHO cells, it inhibited apoptosis induced by the overexpression of human proapoptotic proteins, Bim and Bax. αA-crystallin inhibited doxorubicin-mediated activation of human procaspase-3 in CHO cells and it activated the PI3K/Akt cell survival pathway by promoting the phosphorylation of PDK1, Akt and phosphatase tensin homologue in HeLa cells. The phosphoinositide 3 kinase (PI3K) activity was increased by αA-crystallin overexpression but the protein content was unaltered. Downregulation of PI3K by the expression of a dominant-negative mutant or inhibition by LY294002 abrogated the ability of αA-crystallin to phosphorylate Akt. These antiapoptotic functions of αA-crystallin were enhanced in a mutant protein (R21A) that shows increased chaperone activity than the wild-type (Wt) protein. Interestingly, a mutant protein (R49A) that shows decreased chaperone activity was far weaker than the Wt protein in its antiapoptotic functions. Together, our study results show that αA-crystallin inhibits apoptosis by enhancing PI3K activity and inactivating phosphatase tensin homologue and that the antiapoptotic function is directly related to its chaperone activity.

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

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • CHO Cells
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Caspase Inhibitors
  • Cricetinae
  • Cricetulus
  • Crystallins / genetics
  • Crystallins / physiology*
  • Cytochromes c / metabolism
  • Doxorubicin / pharmacology
  • Enzyme Activation / genetics
  • Enzyme Inhibitors / metabolism
  • HeLa Cells
  • Humans
  • Membrane Proteins / metabolism
  • Mitochondria / metabolism
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Transport
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • bcl-2-Associated X Protein / metabolism


  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • CRYAA protein, human
  • Caspase Inhibitors
  • Crystallins
  • Enzyme Inhibitors
  • Membrane Proteins
  • PDK1 protein, human
  • Proto-Oncogene Proteins
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • bcl-2-Associated X Protein
  • Doxorubicin
  • Cytochromes c
  • Phosphatidylinositol 3-Kinase
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Caspase 3
  • Caspase 9