Mice Deficient in the Putative Phospholipid Flippase ATP11C Exhibit Altered Erythrocyte Shape, Anemia, and Reduced Erythrocyte Life Span*

Abstract

Background: Asymmetrical distribution of specific phospholipids between the two leaflets of biological membranes is generated and maintained by transporters. Results: A mutation in murine Atp11c results in altered morphology and shortened life span of erythrocytes. Conclusion: Phospholipid transport by ATP11C maintains phospholipid asymmetry in erythrocytes. Significance: Defects in phospholipid transport across the cell membrane can lead to anemia.

Exposure of phosphatidylserine on the cell surface

“…On the other hand, and ATP11C-null mice suffer from B-cell lymphopenia, cholestasis, anemia, dystocia and hepatocellular carcinoma. [86][87][88][89] In ATP11C-null B cells and erythrocytes, the flippase activity is reduced and the population of erythrocytes that expose PtdSer is slightly increased. 88,89 How this small effect on flippase activity in ATP11C − / − cells leads to the strong phenotypes seen in ATP11C-null mice is unclear.…”

“…[86][87][88][89] In ATP11C-null B cells and erythrocytes, the flippase activity is reduced and the population of erythrocytes that expose PtdSer is slightly increased. 88,89 How this small effect on flippase activity in ATP11C − / − cells leads to the strong phenotypes seen in ATP11C-null mice is unclear. Lymphocytes or erythrocytes might express only the ATP11C flippase at a specific developmental stage; an ATP11C-null mutation may cause the PtdSer exposure in cells at this stage, leading macrophages to recognize and engulf these cells or causing the destabilization and abnormal assembly of plasma-membrane proteins.…”

ATP11C mutation is responsible for the defect in phosphatidylserine uptake in UPS-1 cells

“…Knockdown by RNA interference or clustered regularly interspaced short palindromic repeat/ CRISPR-associated protein-9 nuclease (CRISPR/Cas9) knockout of CDC50A dramatically decreases PS-fl ipping activity in several cell types (our unpublished observations) ( 19 ). Moreover, ATP11C defi ciency also decreases PSfl ipping activity (17)(18)(19). Therefore, we hypothesized that the defect in the uptake of PS in UPS-1 cells might result from a defect in plasma membrane-localizing PS-fl ipping P4-ATPases (ATP11A and ATP11C) or a defect in CDC50A, which is required for delivery of P4-ATPases to the plasma membrane.…”

“…1A ). ATP11C appears to be a critical protein for PS fl ipping at the plasma membrane in multiple cell types: 1 ) some phenotypes of the ATP11C mutant mice cannot be suppressed by the presence of endogenous ATP11A ( 17,18 ), and 2 ) degradation of ATP11C by caspase is responsible for PS exposure to the outer leafl et of the plasma membrane in apoptotic cells ( 19 ).…”

Inner workings and biological impact of phospholipid flippases

“…Note that low scramblase activity is a prerequisite for preserving the asymmetric lipid arrangements created by unidirectional P 4 -ATPase flippases that operate in late secretory and endosomal orgnanelles. Yabas et al, 2011;Segawa et al, 2014;Yabas et al, 2014 C. elegans A. thaliana Human CDC50A, CDC50B and CDC50C are also referred to as TMEM30A, TMEM30B and TMEM30C, respectively. SV, postGolgi secretory vesicle; PM, plasma membrane; Disk, photo-receptor disk membrane; EE, early endosome; RE, recycling endosome; LE, late endosomes; CL, cardiolipin; LPC, lyso-phosphatidylcholine; LPE, lyso-phosphatidylethanolamine; LPS, lyso-phosphatidylserine; n.d., not defined.…”