QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 19, Issue 2, 691-700, February 2008

This Article Full Text Full Text (PDF) All Versions of this Article: E07-08-0823v1 19/2/691    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lam, D. Articles by Golstein, P. PubMed PubMed Citation Articles by Lam, D. Articles by Golstein, P.

The Inositol 1,4,5-Trisphosphate Receptor Is Required to Signal Autophagic Cell Death

Centre d'Immunologie de Marseille-Luminy, 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

Submitted August 24, 2007; Revised October 26, 2007; Accepted November 29, 2007
Monitoring Editor: Carole Parent

The signaling pathways governing 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)

Abbreviations used: ACD, autophagic cell death; CsA, cyclosporin A; DIF, differentiation-inducing factor; IP3R, inositol 1,4,5-trisphosphate receptor; NCD, necrotic cell death; Tg, thapsigargin.