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Vol. 19, Issue 10, 4404-4420, October 2008

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Calnexin Is Involved in Apoptosis Induced by Endoplasmic Reticulum Stress in the Fission Yeast

Department of Biochemistry, Université de Montréal, Montréal, QC H3C 3J7, Canada

Submitted February 21, 2008; Revised August 1, 2008; Accepted August 4, 2008
Monitoring Editor: Jeffrey L. Brodsky

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.

* Present address: Faculty of Law, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Québec H3C 3J7, Canada.

Address correspondence to: Luis A. Rokeach (luis.rokeach{at}umontreal.ca)

Abbreviations used: aa, amino acid; BiP, immunoglobulin binding protein; cnx1⁺, S. pombe gene encoding calnexin; Cnx1p, S. pombe calnexin; DAPI, 4',6-diamidino-2-phenylindole; DHR123, dihydrorhodamine123; ER, endoplasmic reticulum; ERAD, ER-associated degradation; FITC-VAD-FMK, valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone; hcd, highly conserved central domain; PDI, protein-disulfide isomerase; ROS, reactive oxygen species; TM, transmembrane domain; TUNEL assay, terminal uridine deoxynucleotidyl transferase dUTP nick end labeling assay; UPR, unfolded protein response.

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