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J. Biol. Chem., Vol. 278, Issue 34, 31745-31755, August 22, 2003

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Caspase-dependent Alterations of Ca²⁺ Signaling in the Induction of Apoptosis by Hepatitis B Virus X Protein^*

Mounia Chami  , Davide Ferrari , Pierluigi Nicotera ¶, Patrizia Paterlini-Bréchot || and Rosario Rizzuto  **

From the Department of Experimental and Diagnostic Medicine, Section of General Pathology and Interdiscipliny Center for the Study of Inflammation, Via Borsari 46, I-44100 Ferrara, Italy, the ^¶Medical Research Council Toxicology Unit, Hodgkin Building University of Leicester, Lancaster Road, LE1 9HN, Leicester United Kingdom, and the ^||INSERM/Pasteur U370, Necker Faculty Institute of Medicine, 75015 Paris, France

The hepatitis B virus X protein (HBx) is a multifunctional protein, acting on different targets (e.g. transcription factors, cytoplasmic kinases, and mitochondrial proteins) and exerting cellular effects as diverse as stimulation of cell proliferation and apoptosis. In its biological effects, the modulation of cellular Ca²⁺ signals has been proposed to be involved, but the direct assessment of Ca²⁺ homeostasis in HBx-transfected cells has not been carried out yet. In this work, we have employed for this purpose aequorin-based recombinant probes specifically targeted to intracellular organelles and microdomains. Using these probes, we observed that overexpression of HBx enhanced agonist-evoked cytosolic Ca²⁺ signals in HepG2 and HeLa cells, without affecting either the steady state of endoplasmic reticulum Ca²⁺ concentration or the kinetics of Ca²⁺ release. Rather, caspase-3-dependent cleavage of the plasma membrane Ca²⁺ ATPase could be demonstrated, and larger rises were detected in the cytoplasmic rim beneath the plasma membrane. In mitochondria, major morphological (fragmentation and swelling) and functional (reduced Ca²⁺ uptake) alterations were detected in HBx-expressing cells. As to the cellular consequences, we observed that HBx-induced apoptosis was markedly reduced when the alterations in Ca²⁺ signaling (e.g. by loading a Ca²⁺ chelator or preventing PMCA cleavage) or the downstream effects (e.g. by inhibiting mitochondrial permeability transition) were prevented. Overall, these results indicate that HBx perturbs intracellular Ca²⁺ homeostasis, acting on the extrusion mechanisms, and that this effect plays an important role in the control of HBx-related apoptosis.

Received for publication, April 22, 2003 , and in revised form, June 9, 2003.

^* This work was supported by Telethon Grants 1285 and GTF01011, the Italian Association for Cancer Research, the Human Frontier Science Program, the Italian Ministry for Education University and Research, and the Italian Space Agency for financial support. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a long term EMBO fellowship.

^** To whom correspondence should be addressed: Dept. of Experimental and Diagnostic Medicine, Section of General Pathology, Via Borsari 46, I-44100 Ferrara, Italy. Tel.: 390532291759; Fax: 390532247278; E-mail: r.rizzuto{at}unife.it.

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