The inositol 1,4,5-trisphosphate receptor is required to signal autophagic cell death.
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 Ca(2+) efflux from endoplasmic reticulum stores to the cytosol. Accordingly, Ca(2+)-related drugs also affected DIF signaling leading to ACD. Thus, in this system, a main pathway signaling ACD requires IP3R and further Ca(2+)-dependent steps. This is one of the first insights in the molecular understanding of a signaling pathway leading to autophagic cell death.
Lam
David
D
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, Aix Marseille Université, Marseille, France.
Kosta
Artemis
A
Luciani
Marie-Françoise
MF
Golstein
Pierre
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004023:Dictyostelium / Q000166:cytology* / Q000235:genetics; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D017125:Genes, Protozoan; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008954:Models, Biological; D016254:Mutagenesis, Insertional / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009336:Necrosis; D015800:Protozoan Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology
D053496:Inositol 1,4,5-Trisphosphate Receptors; D015800:Protozoan Proteins; D004533:Egtazic Acid; D019284:Thapsigargin; D016572:Cyclosporine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid