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Published online 13 November 2006. doi:10.1083/jcb.200601024
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 4, 595-605
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Article

Calpain is required for macroautophagy in mammalian cells



Francesca Demarchi1, Cosetta Bertoli1, Tamara Copetti1, Isei Tanida2, Claudio Brancolini3, Eeva-Liisa Eskelinen4, and Claudio Schneider1,3

1 Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie, 34012 Trieste, Italy
2 Department of Biochemistry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
3 Dipartimento di Scienze e Tecnologie Biomediche, Universitá degli Studi di Udine, 33100 Udine, Italy
4 Department of Biological and Environmental Sciences, Division of Biochemistry, 00014 University of Helsinki, Helsinki, Finland

Correspondence to Claudio Schneider: schneide{at}lncib.it

Ubiquitously expressed micro- and millicalpain, which both require the calpain small 1 (CAPNS1) regulatory subunit for function, play important roles in numerous biological and pathological phenomena. We have previously shown that the product of GAS2, a gene specifically induced at growth arrest, is an inhibitor of millicalpain and that its overexpression sensitizes cells to apoptosis in a p53-dependent manner (Benetti, R., G. Del Sal, M. Monte, G. Paroni, C. Brancolini, and C. Schneider. 2001. EMBO J. 20:2702–2714). More recently, we have shown that calpain is also involved in nuclear factor {kappa}B activation and its relative prosurvival function in response to ceramide, in which calpain deficiency strengthens the proapoptotic effect of ceramide (Demarchi, F., C. Bertoli, P.A. Greer, and C. Schneider. 2005. Cell Death Differ. 12:512–522). Here, we further explore the involvement of calpain in the apoptotic switch and find that in calpain-deficient cells, autophagy is impaired with a resulting dramatic increase in apoptotic cell death. Immunostaining of the endogenous autophagosome marker LC3 and electron microscopy experiments demonstrate that autophagy is impaired in CAPNS1-deficient cells. Accordingly, the enhancement of lysosomal activity and long-lived protein degradation, which normally occur upon starvation, is also reduced. In CAPNS1-depleted cells, ectopic LC3 accumulates in early endosome-like vesicles that may represent a salvage pathway for protein degradation when autophagy is defective.

Abbreviations used in this paper: 3MA, 3-methyladenine; AV, autophagic vacuole; CAPNS, calpain small; EBSS, Earle's balanced salt solution; MEF, mouse embryonic fibroblast; PI, propidium iodide.


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