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Heat-shock protein 70 antagonizes apoptosis-inducing factor
L Ravagnan1, S Gurbuxani, S A Susin
1CNRS UMR 1599, Institute Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille Desmoulins, 94805 Villejuif, France.
Nature Cell Biology
|September 5, 2001
Summary
Heat-shock protein 70 (Hsp70) inhibits apoptosis not only by targeting Apaf-1 but also by interacting with apoptosis-inducing factor (AIF). This study reveals Hsp70
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Heat-shock protein 70 (Hsp70) is known to inhibit apoptosis by binding Apaf-1.
- The complete mechanism of Hsp70's anti-apoptotic function is not fully understood.
Purpose of the Study:
- To investigate if Hsp70 targets proteins other than Apaf-1.
- To determine Hsp70's role in caspase-independent apoptosis mediated by AIF.
Main Methods:
- Overexpression of Hsp70 in Apaf-1-/- cells.
- Cell-free assays to assess AIF-induced chromatin condensation.
- Ligand blots and co-immunoprecipitation to study Hsp70-AIF interaction.
- Anti-sense Hsp70 cDNA to reduce endogenous Hsp70 expression.
Main Results:
- Hsp70 overexpression protected cells against serum withdrawal-induced death, independent of Apaf-1.
- Hsp70 directly interacted with AIF and inhibited AIF-induced chromatin condensation.
- Reduced Hsp70 expression increased sensitivity to AIF-mediated cell death.
- The ATP-binding domain of Hsp70 was dispensable for AIF inhibition but required for Apaf-1 binding.
Conclusions:
- Hsp70 inhibits apoptosis through mechanisms beyond Apaf-1 interaction.
- Hsp70 directly interferes with the function of apoptosis-inducing factor (AIF).
- Hsp70 represents a potential therapeutic target for modulating apoptosis.