Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis

Yousefi, S. et al., Nature Cell Biol. 8, 1124–1132 (2006)

Abstract

Programmed cell death can be divided into several categories including typeⅠ (apoptosis) and typeⅡ(autophagic death).  Previous studies indicated potential interconnection between autophagy and apoptosis (1,2).  However, whether autophagy could promote apoptosis remains unknown.  Autophagy-related gene (Atg) 5 has been characterized as a protein specifically required for autophagosome formation.  In this paper, the authors demonstrated that overexpression of Atg5 sensitized cells to apoptotic death in response to anticancer drug treatment, and that silencing of the Atg5 gene resulted in marked resistance to chemotherapy, suggesting that Atg5 is more than an autophagy factor.  A fragment of Atg5 with a relative molecular mass of 24K was found in cells treated with apoptotic stimuli.  Sequence analysis and proteolytic assays showed that the full-length 33K Atg5 was cleaved by calcium-dependent proteases calpain-1 and -2.  A high level of antiapoptotic Bcl-2 protein protected cells from the death-inducing activity of the truncated Atg5, but it did not affect the cleavage of endogenous Atg5, indicating that Atg5 cleavage occurs in a proapoptotic pathway upstream of Bcl-2 activation and precedes the mitochondrial apoptosis.  Indeed, the authors found that, during apoptosis, the truncated Atg5 translocated to mitochondria, bound to Bcl-X_L, and induced cytochrome c release into cytosol and caspase activation.  Together, these results provide molecular insight into the functional roles of calpains and Atg5 in regulating proapoptotic signaling, and suggest that cells with elevated amounts of Atg5 exhibit increased likelihood undergoing apoptosis.  This finding may unravel the biochemical processes of chemotherapy and have potential importance for the treatment of cancer.

References

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2.      Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927-939 (2005).