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MBC in Press, published online ahead of print December 12, 2007
Mol. Biol. Cell 10.1091/mbc.E07-08-0823

A more recent version of this article appeared on February 1, 2008
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Submitted on August 24, 2007
Revised on October 26, 2007
Accepted on November 29, 2007

The IP3 Receptor Is Required to Signal Autophagic Cell Death

David Lam, Artemis Kosta, Marie-Françoise Luciani, and Pierre Golstein

Centre d’Immunologie de Marseille-Luminy (CIML), Institut National de la Santé et de la Recherche Médicale U631, and Centre National de la Recherche Scientifique Unité Mixte de Recherche 6102, Faculté des Sciences de Luminy, Aix Marseille Université, F-13288 Marseille, France

Monitoring Editor: Carole Parent

The signaling pathways governing the pathophysiologically important autophagic (ACD) and necrotic (NCD) cell death are not entirely known. In the Dictyostelium eukaryote model which benefits from both unique analytical and genetic advantages and absence of potentially interfering apoptotic machinery, the differentiation factor DIF leads from starvation-induced autophagy to ACD, or, if atg1 is inactivated, to NCD. Here, through random insertional mutagenesis, we found that inactivation of the iplA gene, the only gene encoding an inositol 1,4,5-trisphosphate receptor (IP3R) in this organism, prevented ACD. The IP3R is a ligand-gated channel governing Ca2+ efflux from endoplasmic reticulum stores to the cytosol. Accordingly, Ca2+-related drugs also affected DIF signaling leading to ACD. Thus, in this system, a main pathway signaling ACD requires IP3R and further Ca2+-dependent steps. This is one of the first insights in the molecular understanding of a signaling pathway leading to autophagic cell death.

Address correspondence to: Pierre Golstein (golstein{at}ciml.univ-mrs.fr)






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