Abstract
Phospholipid scramblase induces nonspecific bidirectional movement of phospholipids across the membrane during cell activation and has been proposed to mediate the appearance of phosphatidylserine (PS) in the plasma membrane outer leaflet during apoptosis, a cell surface change that is critical for apoptotic cell removal. We report here that protein kinase C (PKC) delta plays an important role in activated transbilayer movement of phospholipids and surface PS exposure by directly enhancing the activity of phospholipid scramblase. Specific inhibition of PKCdelta by rottlerin prevented both apoptosis- and activation-induced scramblase activity. PKCdelta was either selectively cleaved and activated in a caspase 3-dependent manner (during apoptosis) or translocated to the plasma membrane (in stimulated cells) and could directly phosphorylate scramblase immunoprecipitated from Jurkat cells. Furthermore, reconstitution of PKCdelta and scramblase, but not scramblase or PKCdelta alone in Chinese hamster ovary cells demonstrated enhanced scramblase activity.
Highlights
Normal circulating blood cells exhibit an asymmetric distribution of phospholipids in the membrane where phosphatidylserine (PS)1 and phosphatidylethanolamine (PE) reside in the inner leaflet and phosphatidylcholine (PC) and sphingomyelin are enriched on the outer leaflet [1, 2]
We have previously shown that PS exposure serves as at least one important and necessary signal for their quiescent removal by phagocytes (8 –11) and have recently identified a novel PS receptor that appears to mediate the recognition of apoptotic cells by phagocytes leading to their subsequent ingestion [12]
A time course of its activity was investigated in neutrophils stimulated with 100 nM fMLP, and in Jurkat cells treated with anti-Fas IgM to induce apoptosis
Summary
Normal circulating blood cells exhibit an asymmetric distribution of phospholipids in the membrane where phosphatidylserine (PS)1 and phosphatidylethanolamine (PE) reside in the inner leaflet and phosphatidylcholine (PC) and sphingomyelin are enriched on the outer leaflet [1, 2]. PKC␦ was either selectively cleaved and activated in a caspase 3-dependent manner (during apoptosis) or translocated to the plasma membrane (in stimulated cells) and could directly phosphorylate scramblase immunoprecipitated from Jurkat cells. We have investigated a potential role for PKC␦ in the regulation of scramblase activity in stimulated cells and in those undergoing apoptosis.
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