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Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis

Nature Cell Biology volume 8, pages 1124–1132 (2006)Cite this article

Abstract

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 (Mr 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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Figure 1: Atg5 regulates cytotoxicity of death triggers.
Figure 2: Apoptosis is associated with Atg5 cleavage as assessed by immunoblotting.
Figure 3: Atg5 is cleaved by calpain.
Figure 4: Enforced expression of truncated Atg5 induces apoptosis, which is blocked by Bcl-2.
Figure 5: Truncated Atg5 translocates to mitochondria, binds to Bcl-xL but not Bax and releases cytochrome c into the cytosol.

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Acknowledgements

This work was supported by the Swiss National Science Foundation (grant No. 310000-107526 and 310000-112078).

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Authors and Affiliations

  1. Department of Pharmacology, University of Bern, Bern, CH-3010, Switzerland

    Shida Yousefi, Inès Schmid & Hans-Uwe Simon

  2. Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, EPGL, University of Geneva, Geneva, 4, CH-1211, Switzerland

    Remo Perozzo & Leonardo Scapozza

  3. Department of Clinical Research, University of Bern, Bern, CH-3010, Switzerland

    Andrew Ziemiecki

  4. Department of Pathology, University of Bern, Bern, CH-3010, Switzerland

    Thomas Schaffner & Thomas Brunner

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Correspondence to Hans-Uwe Simon.

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Yousefi, S., Perozzo, R., Schmid, I. et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 8, 1124–1132 (2006). https://doi.org/10.1038/ncb1482

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