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BAR: An apoptosis regulator at the intersection of caspases and Bcl-2 family proteins

H Zhang1, Q Xu, S Krajewski

  • 1Program on Apoptosis and Cell Death Regulation, The Burnham Institute, La Jolla, CA 92037, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 16, 2000
PubMed

Insights

BAR protein inhibits cell death by linking the intrinsic and extrinsic apoptosis pathways. This novel scaffold protein interacts with Bcl-2 family proteins and death effector domains, bridging key apoptosis regulators.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Apoptosis, or programmed cell death, occurs via intrinsic (mitochondria-dependent) and extrinsic (receptor-mediated) pathways.
  • The extrinsic pathway involves death receptors and death effector domains (DEDs), recruiting procaspases-8 and -10.
  • The intrinsic pathway is regulated by Bcl-2 family proteins, controlling mitochondrial release of caspase activators.

Purpose of the Study:

  • To identify novel regulators of apoptosis.
  • To characterize the function and mechanism of a newly identified apoptosis inhibitor, BAR.
  • To investigate BAR's role in bridging the intrinsic and extrinsic apoptosis pathways.

Main Methods:

  • Yeast-based genetic screening to identify inhibitors of Bax-induced cell death.
  • Mammalian cell culture and yeast assays to assess apoptosis.
  • Co-immunoprecipitation and protein interaction studies to analyze protein complex formation.

Main Results:

  • BAR protein identified as an inhibitor of Bax-induced cell death.
  • BAR contains a SAM domain interacting with Bcl-2 and Bcl-X(L), suppressing cell death.
  • BAR possesses a DED-like domain interacting with procaspases, inhibiting Fas-induced apoptosis.
  • BAR forms a complex bridging procaspase-8 and Bcl-2, acting as a scaffold protein.

Conclusions:

  • BAR functions as a scaffold protein, linking the intrinsic and extrinsic apoptosis pathways.
  • BAR's ability to bridge these pathways suggests a novel regulatory mechanism in cell death.
  • BAR's localization to intracellular membranes where Bcl-2 resides supports its role in integrating apoptosis signaling.

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