An Apoptotic ‘Eat Me’ Signal: Phosphatidylserine Exposure

Flippases translocate phosphatidylserine (PtdSer) and phosphatidylethanolamine (PtdEtn) from outer to inner leaflets of the plasma membrane, keeping these lipids in the inner leaflet. Recent data indicate that ATP11C, a member of P4-type ATPases, together with CDC50A (cell division cycle protein 50A), functions as a flippase. Scramblases nonspecifically and bidirectionally translocate phospholipids between inner and outer leaflets of the plasma membranes. Members of TMEM16 and Xkr families were shown to support Ca2+- and caspase-dependent scrambling of phospholipids, respectively. When cells undergo apoptosis, PtdSer is exposed to work as an ‘eat me’ signal. Recent data indicate that for apoptotic PtdSer exposure, caspases inactivate the flippase, and activate the scramblase by cleavage. Apoptosis and the clearance of apoptotic cells are essential processes in animal development and homeostasis. For apoptotic cells to be cleared, they must display an ‘eat me’ signal, most likely phosphatidylserine (PtdSer) exposure, which prompts phagocytes to engulf the cells. PtdSer, which is recognized by several different systems, is normally confined to the cytoplasmic leaflet of the plasma membrane by a ‘flippase’; apoptosis activates a ‘scramblase’ that quickly exposes PtdSer on the cell surface. The molecules that flip and scramble phospholipids at the plasma membrane have recently been identified. Here we discuss recent findings regarding the molecular mechanisms of apoptotic PtdSer exposure and the clearance of apoptotic cells. Apoptosis and the clearance of apoptotic cells are essential processes in animal development and homeostasis. For apoptotic cells to be cleared, they must display an ‘eat me’ signal, most likely phosphatidylserine (PtdSer) exposure, which prompts phagocytes to engulf the cells. PtdSer, which is recognized by several different systems, is normally confined to the cytoplasmic leaflet of the plasma membrane by a ‘flippase’; apoptosis activates a ‘scramblase’ that quickly exposes PtdSer on the cell surface. The molecules that flip and scramble phospholipids at the plasma membrane have recently been identified. Here we discuss recent findings regarding the molecular mechanisms of apoptotic PtdSer exposure and the clearance of apoptotic cells. an evolutionarily conserved cell death process that removes unwanted or harmful cells. This process involves cell shrinkage, chromatin condensation, DNA fragmentation, and blebbing of plasma membranes. Apoptotic cells are engulfed by macrophages before they rupture. This differs from necrosis, in which cells swell and plasma membranes are ruptured, spilling out cellular contents. a family of cysteine proteases that carry a cysteine residue at the active site, and cleave after aspartic acid. At least 12 members exist in the human caspase family. Some of them are involved in inflammation, while others are involved in apoptosis. a type I membrane protein that belongs to the Ig superfamily, also called integrin-associated protein (IAP). It is expressed ubiquitously, in particular, in human tumor cells. a type I membrane protein that belongs to the Ig superfamily, and carries ITIM motifs in the cytoplasmic region. It is expressed by natural killer (NK) cells, T cell subsets, B cells, dendritic cells, mast cells, granulocytes, and monocytes. cell division cycle protein 50A, also called TMEM30A (Transmembrane protein 30A). It carries two transmembrane regions with cytosolic N and C termini. Identified as one of cold-sensitive cell division cycle (cdc) mutants in yeast, it associates with Type IV P-type ATPases, and is involved in lipid transport. Humans and mice carry three genes: CDC50A, -50B, and -50C. a process in which apoptotic cells are phagocytosed. It comes from ‘effere’ in Latin, which means ‘bury’ or ‘take to the grave’. immunoreceptor tyrosine-based inhibitory motif composed of a conserved sequence of ‘S/I/V/LxYxxI/V/L’ that mediates inhibitory signals. Upon ligand engagement, its tyrosine residue is phosphorylated by src kinase, which recruits tyrosine phosphatases to downregulate the signal. cells that engulf and digest dead cells and foreign pathogens. In mammals, professional phagocytes such as macrophages and immature dendritic cells aggressively engulf apoptotic cells. Fibroblasts and epithelial cells also engulf apoptotic cells, but only weakly. is one of the major phospholipids at the plasma membrane. It is synthesized in the ER by two distinct PtdSer synthases from PtdCho or PtdEtn. PtdSer is catalyzed to PtdEtn by PtdSer decarboxylase at the mitochondrial inner membranes. human P-type ATPase superfamily is composed of 36 members that are phylogenetically divided into five subfamilies (P1–P5). The P-type ATPases have ten transmembrane regions and a cytoplasmic ATPase domain composed of actuator (A), nucleotide-binding (N), and phosphorylation (P) domains. They transport ions or phospholipids across lipid bilayers in an ATP-dependent manner. proteins that nonspecifically and bidirectionally translocate phospholipids between outer and inner leaflets of plasma membranes. signal regulatory protein α, a receptor-type transmembrane protein that belongs to the Ig superfamily. It transduces negative signals in the tyrosine kinase-coupled signaling pathway. systemic lupus erythematosus. An autoimmune disease caused by a failure of self-tolerance, leading to the production of antibodies against DNA, nuclei, and phospholipids. Immune complexes are deposited in tissues such as the kidney, skin, lung, and blood vessels, inducing inflammation. SLE mainly affects females in their reproductive years (aged 15–35 years).