Nature Cell Biology
- 8, 1124 - 1132 (2006)
Published online: 24 September 2006; | doi:10.1038/ncb1482
Calpain-mediated cleavage of Atg5 switches autophagy to apoptosisShida Yousefi1, Remo Perozzo2, Inès Schmid1, Andrew Ziemiecki3, Thomas Schaffner4, Leonardo Scapozza2, Thomas Brunner4 & Hans-Uwe Simon11
Department of Pharmacology, University of Bern, CH-3010 Bern, Switzerland. 2
Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, EPGL, University of Geneva, CH-1211 Geneva 4, Switzerland. 3
Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland. 4
Department of Pathology, University of Bern, CH-3010 Bern, Switzerland.
Correspondence should be addressed to Hans-Uwe Simon hus@pki.unibe.ch Autophagy-related gene (Atg) 5 is a gene product required for the formation of autophagosomes. Here, we report that Atg5, in addition to the promotion of autophagy, enhances susceptibility towards apoptotic stimuli. Enforced expression of Atg5-sensitized tumour cells to anticancer drug treatment both in vitro and in vivo. In contrast, silencing the Atg5 gene with short interfering RNA (siRNA) resulted in partial resistance to chemotherapy. Apoptosis was associated with calpain-mediated Atg5 cleavage, resulting in an amino-terminal cleavage product with a relative molecular mass of 24,000 (M
r 24K). Atg5 cleavage was observed independent of the cell type and the apoptotic stimulus, suggesting that calpain activation and Atg5 cleavage are general phenomena in apoptotic cells. Truncated Atg5 translocated from the cytosol to mitochondria, associated with the anti-apoptotic molecule Bcl-xL and triggered cytochrome c release and caspase activation. Taken together, calpain-mediated Atg5 cleavage provokes apoptotic cell death, therefore, represents a molecular link between autophagy and apoptosis — a finding with potential importance for clinical anticancer therapies.
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