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J. Biol. Chem., Vol. 281, Issue 5, 2693-2700, February 3, 2006

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Endoplasmic Reticulum Stress Induces Apoptosis by an Apoptosome-dependent but Caspase 12-independent Mechanism^*

Federica Di Sano¹, Elisabetta Ferraro^¶2, Roberta Tufi, Tilmann Achsel^¶, Mauro Piacentini^||, and Francesco Cecconi, An Associate Telethon Scientist^¶3

From the Department of Biology, University of Tor Vergata, the Dulbecco Telethon Institute at the Department of Biology, University of Tor Vergata, the ^¶Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, and the ^||National Institute for Infectious Diseases IRCCS "L. Spallanzani", 00100 Rome, Italy

The endoplasmic reticulum (ER) is the cellular site of polypeptide folding and modification. When these processes are hampered, an unfolded protein response (UPR) is activated. If the damage is too broad, the mammalian UPR launches the apoptotic program. As a consequence, mobilization of ER calcium stores sensitizes mitochondria to direct proapoptotic stimuli. We make use of a mouse Apaf1-deficient cell system of proneural origin to understand the roles played in this context by the apoptosome, the most studied apoptotic machinery along the mitochondrial pathway of death. We show here that in the absence of the apoptosome ER stress induces cytochrome c release from the mitochondria but that apoptosis cannot occur. Under these circumstances, Grp78/BiP and GADD153/CHOP, both hallmarks of UPR, are canonically up-regulated, and calcium is properly released from ER stores. We also demonstrate that caspase 12, a protease until now believed to play a central role in the initiation of ER stress-induced cell death in the mouse system, is dispensable for the mitochondrial pathway of death to take place.

Received for publication, August 18, 2005 , and in revised form, November 14, 2005.

^* This work was supported in part by the Telethon Foundation (Grant S99038), the Compagnia di San Paolo, the Italian Ministry of University and Research (MIUR) through the 2001 program of Basic Research Funding (FIRB, Grant RBAU01FZMZ), and the Associazione Italiana Ricerca sul Cancro (AIRC). 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.

¹ An AIRC fellow.

² Funded by Fondazione Santa Lucia.

³ To whom correspondence should be addressed: Dulbecco Telethon Institute at the Dept. of Biology, University of Tor Vergata, via della Ricerca Scientifica, 00133 Rome, Italy. Tel.: 39-06-72594230; Fax: 39-06-2023500; E-mail: fcecconi{at}dti.telethon.it or francesco.cecconi{at}uniroma2.it.

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