Phospholipid scramblase

Recent findings suggest that PLSCR3 is involved in regulation of biosynthesis of cardiolipin in mitochondria, and its overexpression in cultured cells resulted in increased cardiolipin synthase[8][9] activity. As cardiolipin is synthesized in the luminal side of inner mitochondrial membrane, a major fraction of this newly synthesized pool of cardiolipin has to be translocated from the inner to the outer mitochondrial membrane. PLSCR3 has been proposed to be involved in this translocation from the inner to the outer membrane that is essential for maintaining the mitochondrial architecture, mass, and transmembrane potential.

Recent findings suggest that PLSCR3 and, to a lesser degree, PLSCR1 are critical to the normal regulation of fat accumulation in mice. In addition to blood cells, PLSCR3 is expressed to a significantly higher level in fat and muscle cells, which are actively involved in fat metabolism. PLSCR3 knockout mice showed an aberrant abdominal fat accumulation, glucose intolerance, insulin resistance, and dyslipidema as compared to controlled mice. Cultured fat cells from PLSCR3 knockout mice were engorged with neutral lipids. Blood plasma of these mice showed elevated levels of non-high-density lipoproteins, cholesterol, triglycerides, non-esterified fatty acids, and leptin, but low adiponectin content. Abdominal fat accumulation with the formation of enlarged lipid engorged adipocytes has emerged as the key risk factor for the onset of type 2 diabetes,[10] which is often a manifestation of a broader underlying metabolic disorder termed as metabolic syndrome. Further studies on the regulation of lipid metabolism by PLSCRs are required to understand the risk for development of similar diseases in humans when PLSCR genes are mutated, leading to a defective expression and/or function of PLSCR proteins.

Upon activation (in platelets) or injury (in erythrocytes, platelets, endothelium, and other cells), certain cells expose the phospholipid phosphatidylserine on their surface and act as catalysts to induce the coagulation cascade. Surface exposure of phosphatidylserine is thought to be brought about by the activation of scramblases. Several enzyme complexes of blood coagulation cascade such as tenase and prothrombinase are activated by the cell surface exposure of the phosphatidylserine. However, the most studied member of the scramblase family PLSCR1 was shown to be defective in translocation of phospholipids when reconstituted into proteoliposomes in vitro. Although recent studies show that PLSCR1 is neither sufficient nor necessary for the phosphatidylserine externalization, the involvement of PLSCR1 in blood coagulation remains elusive, raising the question of additional membrane components in the externalization pathway. To date, no report is available on the involvement of any other identified member of PLSCRs in blood clotting.

Apoptotic cell death is characterized by a proteolytic caspase cascade that emanates from either an extrinsic or an intrinsic pathway. The extrinsic pathway is initiated by membrane bound death receptors, leading to activation of caspase 8, whereas the intrinsic pathway is triggered by DNA damaging drugs and UV radiation, leading to mitochondrial depolarization and subsequent activation of caspase 9. PLSCRs are supposed to play an important role in both intrinsic and extrinsic apoptotic responses that are linked to each other via the activation of caspase 8. Activated caspase 8 causes the cleavage of the amino terminal portion of the cytosolic protein Bid to generate t-Bid that is translocated into mitochondria during apoptosis. hPLSCR1 and its mitochondrial counterpart hPLSCR3 are phosphorylated by PKCδ during PKC-δ-induced apoptosis. While the consequence of hPLSCR1 phosphorylation and its mechanism of action during cellular apoptotic response remain unclear, phosphorylated hPLSCR3 is thought to facilitate mitochondrial targeting of t-Bid that is an essential requirement in caspase 8-mediated apoptosis. The active t-Bid fragment is shown to localize to mitochondria through a positive interaction with cardiolipin. This activated t-Bid induces activation of Bax and Bak proteins to form cytochrome c channels that facilitate the release of cytochrome c during apoptosis.

An early morphological event in both the extrinsic and the intrinsic apoptotic pathways is the surface exposure of the phospholipid phosphatidylserine, about 96% of which normally reside in the cytosolic leaflet of the plasma membrane. Phosphatidylserine is translocated to the exoplasmic leaflet by the activation of scramblases, leading to pro-coagulant properties and providing a phagocytic signal to the macrophages that engulf and clear the apoptotic cells. The involvement of other associated proteins aiding scrambling activity cannot be ruled out.