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

Author:

Lam David1,Kosta Artemis1,Luciani Marie-Françoise1,Golstein Pierre1

Affiliation:

1. 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

Abstract

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.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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