Calnexin is involved in apoptosis induced by endoplasmic reticulum stress in the fission yeast

Stress conditions affecting the functions of the endoplasmic reticulum (ER) cause the accumulation of unfolded proteins. ER stress is counteracted by the unfolded-protein response (UPR). However, under prolonged stress the UPR initiates a proapoptotic response. Mounting evidence indicate that the ER...

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Bibliographic Details
Published in:Molecular biology of the cell 2008-10, Vol.19 (10), p.4404-4420
Main Authors: Guérin, Renée, Arseneault, Geneviève, Dumont, Stéphane, Rokeach, Luis A
Format: Article
Language:English
Subjects:
Apoptosis
Calnexin - physiology
Cell Death
Cell Survival
Cytosol - metabolism
Endoplasmic Reticulum - metabolism
Gene Expression Regulation, Fungal
HMGB1 Protein - metabolism
Humans
Models, Biological
Mutation
Plasmids
Protein Denaturation
Schizosaccharomyces - metabolism
Schizosaccharomyces pombe Proteins - metabolism
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Summary:Stress conditions affecting the functions of the endoplasmic reticulum (ER) cause the accumulation of unfolded proteins. ER stress is counteracted by the unfolded-protein response (UPR). However, under prolonged stress the UPR initiates a proapoptotic response. Mounting evidence indicate that the ER chaperone calnexin is involved in apoptosis caused by ER stress. Here, we report that overexpression of calnexin in Schizosaccharomyces pombe induces cell death with apoptosis markers. Cell death was partially dependent on the Ire1p ER-stress transducer. Apoptotic death caused by calnexin overexpression required its transmembrane domain (TM), and involved sequences on either side of the ER membrane. Apoptotic death caused by tunicamycin was dramatically reduced in a strain expressing endogenous levels of calnexin lacking its TM and cytosolic tail. This demonstrates the involvement of calnexin in apoptosis triggered by ER stress. A genetic screen identified the S. pombe homologue of the human antiapoptotic protein HMGB1 as a suppressor of apoptotic death due to calnexin overexpression. Remarkably, overexpression of human calnexin in S. pombe also provoked apoptotic death. Our results argue for the conservation of the role of calnexin in apoptosis triggered by ER stress, and validate S. pombe as a model to elucidate the mechanisms of calnexin-mediated cell death.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E08-02-0188