A nonapoptotic role for BAX and BAK in eicosanoid metabolism

ACS Chem Biol. 2015 Jun 19;10(6):1398-403. doi: 10.1021/acschembio.5b00168. Epub 2015 Apr 6.

Abstract

BCL-2 proteins are key regulators of programmed cell death. The interplay between pro and antiapoptotic BCL-2 members has important roles in many cancers. In addition to their apoptotic function, recent evidence supports key nonapoptotic roles for several BCL-2 proteins. We used an unbiased lipidomics strategy to reveal that the proapoptotic proteins BAX, and to a lesser extent BAK, regulate the cellular inflammatory response by mediating COX-2 expression and prostaglandin biosynthesis. COX-2 upregulation in response to the bacterial endotoxin lipopolysaccharide is blunted in the absence of BAX, and Bax(-/-) mouse embryonic fibroblasts display altered kinetics of NFκB and MAPK signaling following endotoxin treatment. Our approach uncovers a novel, nonapoptotic function for BAX in regulation of the cellular inflammatory response and suggests that inflammation and apoptosis are more tightly connected than previously anticipated.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Eicosanoids / metabolism*
  • Embryo, Mammalian
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Gene Expression Regulation
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Signal Transduction
  • bcl-2 Homologous Antagonist-Killer Protein / deficiency
  • bcl-2 Homologous Antagonist-Killer Protein / genetics*
  • bcl-2-Associated X Protein / deficiency
  • bcl-2-Associated X Protein / genetics*

Substances

  • BAK1 protein, human
  • Bax protein, mouse
  • Eicosanoids
  • Lipopolysaccharides
  • NF-kappa B
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Mitogen-Activated Protein Kinases