Figure 5.

Mechanisms of CD47-induced caspase-independent cell death.CD47 induces a caspase-independent cell death, characterized by intact or slightly modified nuclei, reduced cell viability (80). The process of cell apoptosis includes PS (phosphatidylserine) exposure, disruption of mitochondrial function, and cytoskeleton rearrangement (1): K+ is a critical component of volume regulatory response, and leakage of K+ is a simple way to accommodate a rapid decrease in cell volume; CD47-induced cell death was dependent on K+ efflux (81); (2) Mechanisms involved in PS exposure remain poorly understood. Veronique M et al. proposed that CD47 ligation initially induce triggering of actin polymerization, perhaps via Cdc42/WASP pathway. This event then leads to mitochondrial changes including matrix swelling and ΔΨm (mitochondrial transmembrane potential) loss, followed by PS exposure or bypass of mitochondria and direct induction of PS externalization (81); (3) In addition, Bcl-2 homology 3 (BH3)-only protein 19 kDa interacting protein-3 (BNIP3) is indispensable for the pro-apoptotic effect of CD47 (82). A simple model-based on the translocation of BNIP3 from the inner surface of the cell membrane to the mitochondria is proposed since BNIP3 can only exert its pro-apoptotic effect at the mitochondria membrane (83).