Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptotic cells are engulfed and digested by macrophages to maintain homeostasis in animals. If dead cells are not engulfed swiftly, they undergo secondary necrosis and release intracellular components that activate the immune system. Apoptotic cells are efficiently cleared due to phosphatidylserine (PtdSer) exposed on the cell surface that acts as an "eat me" signal. PtdSer is exposed through the activation of phospholipid scramblase and the inactivation of phospholipid flippase, which are both caspase-mediated events. Macrophages express a variety of molecules to recognize PtdSer, and use a sophisticated mechanism to engulf apoptotic cells. In red blood cells, the nucleus is lost when it is extruded as a pyrenocyte during definitive erythropoiesis. These pyrenocytes (nuclei surrounded by plasma membrane) also expose PtdSer on their surface and are efficiently engulfed by macrophages in a PtdSer-dependent manner. Macrophages transfer the engulfed apoptotic cell or pyrenocyte into lysosomes, where the components of the dead cell or pyrenocyte are degraded. If lysosomes cannot digest the DNA from apoptotic cells or pyrenocytes, the undigested DNA accumulates in the lysosome and activates macrophages to produce type I interferon (IFN) via a STING-dependent pathway; in embryos, this causes severe anemia. Here, we discuss how macrophages clear apoptotic cells and pyrenocytes.
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PMID:Clearance of Apoptotic Cells and Pyrenocytes. 2643 71

ATP-dependent phospholipid flippase activity crucial for generating lipid asymmetry was first detected in red blood cell (RBC) membranes, but the P4-ATPases responsible have not been directly determined. Using affinity-based MS, we show that ATP11C is the only abundant P4-ATPase phospholipid flippase in human RBCs, whereas ATP11C and ATP8A1 are the major P4-ATPases in mouse RBCs. We also found that ATP11A and ATP11B are present at low levels. Mutations in the gene encoding ATP11C are responsible for blood and liver disorders, but the disease mechanisms are not known. Using heterologous expression, we show that the T415N substitution in the phosphorylation motif of ATP11C, responsible for congenital hemolytic anemia, reduces ATP11C expression, increases retention in the endoplasmic reticulum, and decreases ATPase activity by 61% relative to WT ATP11C. The I355K substitution in the transmembrane domain associated with cholestasis and anemia in mice was expressed at WT levels and trafficked to the plasma membrane but was devoid of activity. We conclude that the T415N variant causes significant protein misfolding, resulting in low protein expression, cellular mislocalization, and reduced functional activity. In contrast, the I355K variant folds and traffics normally but lacks key contacts required for activity. We propose that the loss in ATP11C phospholipid flippase activity coupled with phospholipid scramblase activity results in the exposure of phosphatidylserine on the surface of RBCs, decreasing RBC survival and resulting in anemia.
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PMID:Identification and functional analyses of disease-associated P4-ATPase phospholipid flippase variants in red blood cells. 3085 Mar 95