Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 19, Issue 2, Pages 691-700Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E07-08-0823
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Funding
- Ligue Nationale Contre le Cancer
- Agence Nationale pour la Recherche [ANR-05-BLAN-0333-01]
- European Community [LSHG-CT-2004-511983]
- Ministerepour la Recherche [ACI BCMS174]
- Canceropole PACA
- Association pour la Recherche sur le Cancer
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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.
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