Abstract
Phospholipid Scramblase 1 (PLSCR1) was initially characterized as a type II transmembrane protein involved in bilayer movements of phospholipids across the plasma membrane leading to the cell surface exposure of phosphatidylserine, but other cellular functions have been ascribed to this protein in signaling processes and in the nucleus. In the present study, expression and functions of PLSCR1 were explored in specialized phagocytic cells of the monocyte/macrophage lineage. The expression of PLSCR1 was found to be markedly increased in monocyte-derived macrophages compared to undifferentiated primary monocytes. Surprisingly, this 3-fold increase in PLSCR1 expression correlated with an apparent modification in the membrane topology of the protein at the cell surface of differentiated macrophages. While depletion of PLSCR1 in the monocytic THP-1 cell-line with specific shRNA did not inhibit the constitutive cell surface exposure of phosphatidylserine observed in differentiated macrophages, a net increase in the FcR-mediated phagocytic activity was measured in PLSCR1-depleted THP-1 cells and in bone marrow-derived macrophages from PLSCR1 knock-out mice. Reciprocally, phagocytosis was down-regulated in cells overexpressing PLSCR1. Since endogenous PLSCR1 was recruited both in phagocytic cups and in phagosomes, our results reveal a specific role for induced PLSCR1 expression in the modulation of the phagocytic process in differentiated macrophages.
Highlights
Phospholipid scramblase 1 (PLSCR1) is a member of a protein family referenced as phospholipid scramblases that are conserved in all eukaryotic organisms
Since this analysis was performed in resting cells, PLSCR1 expression was examined in lysates from HPB-ALL T cells and THP-1 cells treated for different time periods with phorbol 12-myristate 13-acetate (PMA)-ionomycin
Since the treated THP-1 cells had a morphologically differentiated macrophage phenotype and showed a decrease in the cell surface expression of CD14, a monocyte marker that is downregulated during differentiation [23,24], these data indicate that PLSCR1 is upregulated during PMA-induced differentiation of the promonocytic THP-1 cells
Summary
Phospholipid scramblase 1 (PLSCR1) is a member of a protein family referenced as phospholipid scramblases that are conserved in all eukaryotic organisms. Phospholipid Scramblase 1 Function in Macrophages terminal extracellular domain (aa 310–318), a single transmembrane helix (aa 291–309) and a long intracytoplasmic N-terminal domain of 290 aa (aa 1–290), containing a cysteine-rich palmitoylation motif (C184CCPCC189) that could stabilize PLSCR1 anchoring in biological membranes [2,3,4]. Scrambling of membrane phospholipids leads to the cell surface exposure of phosphatidylserine (PS), a critical signal for biological processes such as cell activation, coagulation, apoptosis and secretion [9,10]. This specific role of PLSCR1 in regulating phospholipid movements within the plasma membrane has been recently challenged in several experimental systems (for reviews, [2,9])
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