BCL-2 family member BOK promotes apoptosis in response to endoplasmic reticulum stress

Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):7201-6. doi: 10.1073/pnas.1421063112. Epub 2015 May 26.

Abstract

B-cell lymphoma 2 (BCL-2) ovarian killer (BOK) is a BCL-2 family protein with high homology to the multidomain proapoptotic proteins BAX and BAK, yet Bok(-/-) and even Bax(-/-)Bok(-/-) and Bak(-/-)Bok(-/-) mice were reported to have no overt phenotype or apoptotic defects in response to a host of classical stress stimuli. These surprising findings were interpreted to reflect functional compensation among the BAX, BAK, and BOK proteins. However, BOK cannot compensate for the severe apoptotic defects of Bax(-/-)Bak(-/-) mice despite its widespread expression. Here, we independently developed Bok(-/-) mice and found that Bok(-/-) cells are selectively defective in their response to endoplasmic reticulum (ER) stress stimuli, consistent with the predominant subcellular localization of BOK at the ER. Whereas Bok(-/-) mouse embryonic fibroblasts exposed to thapsigargin, A23187, brefeldin A, DTT, geldanamycin, or bortezomib manifested reduced activation of the mitochondrial apoptotic pathway, the death response to other stimuli such as etoposide, staurosporine, or UV remained fully intact. Multiple organs in Bok(-/-) mice exhibited resistance to thapsigargin-induced apoptosis in vivo. Although the ER stress agents activated the unfolded protein response, both ATF4 and CHOP activation were diminished in Bok(-/-) cells and mice. Importantly, BAX and BAK were unable to compensate for the defective apoptotic response to ER stress observed in SV40-transformed and primary Bok(-/-) cells, and in vivo. These findings support a selective and distinguishing role for BOK in regulating the apoptotic response to ER stress, revealing--to our knowledge--the first bona fide apoptotic defect linked to Bok deletion.

Keywords: BCL-2 family; BOK; apoptosis; endoplasmic reticulum stress; unfolded protein response.

Publication types

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

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Annexin A5 / pharmacology
  • Apoptosis / physiology*
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cells, Cultured
  • Endoplasmic Reticulum / enzymology
  • Endoplasmic Reticulum / metabolism*
  • Enzyme Activation
  • Mice
  • Mice, Knockout
  • Oxidative Stress*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Transcription Factor CHOP / metabolism

Substances

  • Annexin A5
  • Atf4 protein, mouse
  • Bok protein, mouse
  • Ddit3 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • Caspase 3
  • Caspase 7