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Examining BCL-2 Family Function with Large Unilamellar Vesicles
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A nonapoptotic role for BAX and BAK in eicosanoid metabolism

Tejia Zhang1, Loren D Walensky2,3, Alan Saghatelian1

  • 1†Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California 92037, United States.

ACS Chemical Biology
|March 28, 2015
PubMed

Insights

The proapoptotic protein BAX regulates inflammation by controlling COX-2 expression and prostaglandin production. This reveals a novel nonapoptotic role for BCL-2 family proteins in the inflammatory response.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Immunology

Background:

  • BCL-2 proteins are crucial regulators of programmed cell death (apoptosis).
  • The balance between proapoptotic and antiapoptotic BCL-2 members is vital in cancer biology.
  • Emerging evidence highlights significant nonapoptotic functions for BCL-2 family proteins.

Purpose of the Study:

  • To investigate potential nonapoptotic roles of BCL-2 proteins.
  • To uncover novel functions of BCL-2 proteins beyond their apoptotic roles.
  • To explore the connection between apoptosis regulators and the cellular inflammatory response.

Main Methods:

  • Utilized an unbiased lipidomics approach to identify novel protein functions.
  • Investigated the role of BCL-2 proteins, specifically BAX and BAK, in regulating inflammatory pathways.
  • Examined COX-2 expression and prostaglandin biosynthesis in the presence and absence of BAX.
  • Analyzed NFκB and MAPK signaling kinetics in Bax(-/-) mouse embryonic fibroblasts treated with lipopolysaccharide.

Main Results:

  • The proapoptotic proteins BAX and BAK were found to regulate the cellular inflammatory response.
  • BAX mediates COX-2 expression and prostaglandin biosynthesis.
  • COX-2 upregulation induced by lipopolysaccharide was diminished in BAX-deficient cells.
  • Bax(-/-) mouse embryonic fibroblasts exhibited altered NFκB and MAPK signaling dynamics post-endotoxin exposure.

Conclusions:

  • BAX plays a novel, nonapoptotic role in regulating the cellular inflammatory response.
  • This study uncovers a previously unappreciated link between apoptosis regulation and inflammation.
  • The findings suggest that BCL-2 family proteins have broader functions in cellular signaling than previously understood.

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