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Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1
B N Chau1, E H Cheng, D A Kerr
1Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Schools of Medicine and Public Health, Baltimore, Maryland 21205, USA.
Abstract:
Bcl-x(L), an antiapoptotic Bcl-2 family member, is postulated to function at multiple stages in the cell death pathway. The possibility that Bcl-x(L) inhibits cell death at a late (postmitochondrial) step in the death pathway is supported by this report of a novel apoptosis inhibitor, Aven, which binds to both Bcl-x(L) and the caspase regulator, Apaf-1. Identified in a yeast two-hybrid screen, Aven is broadly expressed and is conserved in other mammalian species. Only those mutants of Bcl-x(L)that retain their antiapoptotic activity are capable of binding Aven. Aven interferes with the ability of Apaf-1 to self-associate, suggesting that Aven impairs Apaf-1-mediated activation of caspases. Consistent with this idea, Aven inhibited the proteolytic activation of caspases in a cell-free extract and suppressed apoptosis induced by Apaf-1 plus caspase-9. Thus, Aven represents a new class of cell death regulator.
Insights
A novel apoptosis inhibitor, Aven, binds to Bcl-x(L) and Apaf-1, suggesting it regulates cell death at a late stage. Aven impairs Apaf-1-mediated caspase activation, representing a new class of cell death regulator.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Bcl-x(L) is an antiapoptotic protein involved in regulating cell death.
- Its function at various stages of the cell death pathway is under investigation.
- The precise mechanisms by which Bcl-x(L) exerts its antiapoptotic effects, particularly at later stages, remain to be fully elucidated.
Purpose of the Study:
- To identify novel regulators of apoptosis.
- To investigate the role of Bcl-x(L) in late-stage cell death.
- To characterize a newly discovered apoptosis inhibitor, Aven.
Main Methods:
- Yeast two-hybrid screening to identify binding partners.
- Biochemical assays to assess protein interactions and enzyme activity.
- Cell-free extracts and apoptosis induction systems to evaluate inhibitor function.
Main Results:
- A novel apoptosis inhibitor, Aven, was identified.
- Aven binds to Bcl-x(L) and the caspase regulator Apaf-1.
- Aven inhibits Apaf-1 self-association and caspase activation, suppressing apoptosis.
- Aven's interaction with Bcl-x(L) requires Bcl-x(L)'s antiapoptotic activity.
Conclusions:
- Aven represents a new class of cell death regulator.
- Aven functions at a post-mitochondrial, late step in the apoptosis pathway.
- Aven's mechanism involves interfering with Apaf-1-mediated caspase activation.