Group IV Phospholipase A2α Controls the Formation of Inter-Cisternal Continuities Involved in Intra-Golgi Transport

The enzyme phospholipase A2 (cPLA2α) is involved in the formation of intercisternal tubules that mediate transport of proteins within the Golgi complex

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 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

Induction of Cellular Senescence by Secretory Phospholipase A2 in Human Dermal Fibroblasts through an ROS-Mediated p53 Pathway

Secretory phospholipase A2 (sPLA2) is involved in various cellular physiological and pathological responses, especially in inflammatory responses. Accumulating evidence suggests that inflammation is an underlying basis for the molecular alterations that link aging and age-related pathological processes. However, the involvement of sPLA2 in cellular senescence is not clear. In this study, we found that sPLA2 treatment induces cellular senescence in human dermal fibroblasts (HDFs), as confirmed by increases in senescence-associated β-galactosidase activity, changes in cell morphology, and upregulation of p53/p21 protein levels. sPLA2-induced senescence was observed in p16-knockdown HDFs and p16-null mouse fibroblasts, but not in p53-knockdown HDFs and p53-null mouse fibroblasts. Treatment with sPLA2 increases reactive oxygen species (ROS) production, and an antioxidant, N-acetylcysteine, inhibits sPLA2-induced cellular senescence. These results suggest that sPLA2 has a role in cellular senescence in HDFs during inflammatory response by promoting ROS-dependent p53 activation and might therefore contribute to inflammatory disorders associated with aging