Abstract
Phosphatidylserine (PS) exposure on the cell surface has been considered a characteristic feature of apoptosis and serves as a molecular cue for engulfment of dying cells by phagocytes. However, the mechanism of PS exposure is still not fully elucidated. Here we show that the cytosolic release from mitochondria of apoptosis-inducing factor (AIF) is required for PS exposure during death receptor-induced apoptosis and for efficient clearance of cell corpses by primary human macrophages. Fas-triggered PS exposure was significantly reduced upon siRNA-mediated silencing of AIF expression and by inhibition of the cytosolic translocation of AIF. In addition, AIF localizes to the plasma membrane upon Fas ligation and promotes activation of phospholipid scrambling activity. Finally, cytosolic stabilization of AIF through interaction with Scythe is shown to be involved in apoptotic PS exposure. Taken together, our results suggest an essential role for AIF and its binding partner Scythe in the pathway leading to apoptotic corpse clearance.
Highlights
Apoptosis is a multistep process characterized by different morphological and biochemical alterations including cell shrinkage, membrane blebbing, nuclear condensation and DNA degradation [1]
These results strongly suggest that apoptosis-inducing factor (AIF), a key mediator of caspase-independent apoptosis-like programmed cell death [17], plays an active role in the pathway leading to PS exposure, confirming the role of mitochondria as critical organelles for signals regulating the phagocytosis process as suggested in previous work [14,18]
This study demonstrates the importance of AIF and its binding partner Scythe for the externalization of PS on the surface of apoptotic cells and the subsequent elimination of these cells by primary human macrophages
Summary
Apoptosis is a multistep process characterized by different morphological and biochemical alterations including cell shrinkage, membrane blebbing, nuclear condensation and DNA degradation [1]. These events are orchestrated by the activity of a family of cysteine proteases called caspases. Death receptor triggering results in the formation of a Death-Inducing Signaling Complex (DISC) leading to activation of caspase-8, the most apical caspase in the extrinsic pathway, while cytochrome c promotes the formation of the apoptosome complex, resulting in capase-9 activation [2] Both pathways converge on the activation of caspase-3, the central ‘‘executioner’’ of apoptosis. Mitochondrial outer membrane permeabilization leads to the release of apoptosis-inducing factor (AIF) resulting in caspase-independent chromatin condensation and DNA fragmentation [3]
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