The human body generates 10-100 billion cells every day, and the same number of cells die to maintain homeostasis in our body. Cells infected by bacteria or viruses also die. The cell death that ...occurs under physiological conditions mainly proceeds by apoptosis, which is a noninflammatory, or silent, process, while pathogen infection induces necroptosis or pyroptosis, which activates the immune system and causes inflammation. Dead cells generated by apoptosis are quickly engulfed by macrophages for degradation. Caspases are a large family of cysteine proteases that act in cascades. A cascade that leads to caspase 3 activation mediates apoptosis and is responsible for killing cells, recruiting macrophages, and presenting an "eat me" signal(s). When apoptotic cells are not efficiently engulfed by macrophages, they undergo secondary necrosis and release intracellular materials that represent a damage-associated molecular pattern, which may lead to a systemic lupus-like autoimmune disease.
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.
Cellular membranes function as permeability barriers that separate cells from the external environment or partition cells into distinct compartments. These membranes are lipid bilayers composed of ...glycerophospholipids, sphingolipids and cholesterol, in which proteins are embedded. Glycerophospholipids and sphingolipids freely move laterally, whereas transverse movement between lipid bilayers is limited. Phospholipids are asymmetrically distributed between membrane leaflets but change their location in biological processes, serving as signalling molecules or enzyme activators. Designated proteins - flippases and scramblases - mediate this lipid movement between the bilayers. Flippases mediate the confined localization of specific phospholipids (phosphatidylserine (PtdSer) and phosphatidylethanolamine) to the cytoplasmic leaflet. Scramblases randomly scramble phospholipids between leaflets and facilitate the exposure of PtdSer on the cell surface, which serves as an important signalling molecule and as an 'eat me' signal for phagocytes. Defects in flippases and scramblases cause various human diseases. We herein review the recent research on the structure of flippases and scramblases and their physiological roles. Although still poorly understood, we address the mechanisms by which they translocate phospholipids between lipid bilayers and how defects cause human diseases.
Apoptosis and autoimmune diseases Nagata, Shigekazu
Annals of the New York Academy of Sciences,
October 2010, Letnik:
1209, Številka:
1
Journal Article
Recenzirano
Every day billions of cells die in our bodies to eliminate those that are harmful, useless, or senescent. The process can be divided into two steps: cell dying and cell clearance. In the first step, ...death machinery is activated in the cells and quickly kills them. During the second step, dead cells are engulfed by phagocytes, and their components are degraded in the lysosomes of the phagocytes. The death mechanism and the clearance of dead cells have been extensively studied. Mouse lines that are deficient in the death or clearance process have been established, and human patients carrying a mutation in the death machinery have been identified. Data from these mutant mice and human patients indicate that defects in cell death or dead‐cell clearance leads to autoimmunity. This review examines the cell death and clearance processes and briefly discusses the diseases they cause.
Efferocytosis and autoimmune disease Kawano, Mahiru; Nagata, Shigekazu
International immunology,
12/2018, Letnik:
30, Številka:
12
Journal Article
Recenzirano
Odprti dostop
An enormous number of cells in the body die by apoptosis during development and under homeostasis. Apoptotic cells are swiftly engulfed by macrophages and digested into units. This removal of ...apoptotic cells is called 'efferocytosis'. For efferocytosis, macrophages recognize phosphatidylserine (PtdSer) exposed on the cell surface as an 'eat me' signal. In healthy cells, PtdSer is exclusively localized to the inner leaflet of the plasma membrane by the action of flippases. When cells undergo apoptosis, caspase cleaves flippases to inactivate them, while it cleaves pro-scramblases to active scramblases, which quickly translocate PtdSer to the cell surface. The PtdSer is then recognized by PtdSer-binding proteins or by PtdSer receptors on macrophages, which subsequently engulf the apoptotic cells. When efferocytosis fails, apoptotic cells can rupture, releasing cellular materials that can evoke an autoimmune response. Thus, a defect in the PtdSer-exposing or PtdSer-recognizing processes triggers autoimmunity, leading to a systemic lupus erythematosus-type autoimmune disease.
In the late 1970s, crude interferon samples were found to exhibit anti-tumour activity. This discovery led to the interferon as a “magic drug” for cancer patients. Many groups, including those in ...Tokyo, Zürich, and San Francisco, attempted to identify human interferon cDNAs. Tadatsugu Taniguchi was the first to announce the cloning of human interferon-β cDNA in the December 1979 issue of Proc. Jpn. Acad. Ser. B. This was followed by the cloning of human interferon-α by a Zürich group and interferon-γ by a group in Genentech in San Francisco. Recombinant interferon proteins were produced on a large scale, and interferon-α was widely used to treat C-type hepatitis patients. The biological functions of interferons were quickly elucidated with the purified recombinant interferons. The molecular mechanisms underlying virus-induced interferon gene expression were also examined using cloned chromosomal genes. The background that led to interferon gene cloning and its impact on cytokine gene hunting is described herein.
To maintain organismal homeostasis, phagocytes engulf dead cells, which are recognized as dead by virtue of a characteristic “eat me” signal exposed on their surface. The dead cells are then ...transferred to lysosomes, where their cellular components are degraded for reuse. Inefficient engulfment of dead cells activates the immune system, causing disease such as systemic lupus erythematosus, and if the DNA of the dead cells is not properly degraded, the innate immune response becomes activated, leading to severe anemia and chronic arthritis. Here, we discuss how the endogenous components of dead cells activate the immune system through both extracellular and intracellular pathways.
Extracellular ATP released from necrotic cells in inflamed tissues activates the P2X7 receptor, stimulates the exposure of phosphatidylserine, and causes cell lysis. Recent findings indicated that ...XK, a paralogue of XKR8 lipid scramblase, forms a complex with VPS13A at the plasma membrane of T cells. Upon engagement by ATP, an unidentified signal(s) from the P2X7 receptor activates the XK‐VPS13A complex to scramble phospholipids, followed by necrotic cell death. P2X7 is expressed highly in CD25+CD4+ T cells but weakly in CD8+ T cells, suggesting a role of this system in the activation of the immune system to prevent infection. On the other hand, a loss‐of‐function mutation in XK or VPS13A causes neuroacanthocytosis, indicating the crucial involvement of XK‐VPS13A‐mediated phospholipid scrambling at plasma membranes in the maintenance of homeostasis in the nervous and red blood cell systems.
The XK‐VPS13A complex is present in plasma membranes of various cells and is activated by extracellular ATP or the stress‐injured plasma membrane. The activated complex scrambles phospholipids to kill regulatory T cells or to repair the plasma membrane. The deficiency of XK or VPS13A causes neuroacanthocytosis in humans.
Xk-related protein (Xkr) 8, a protein carrying 10 transmembrane regions, is essential for scrambling phospholipids during apoptosis. Here, we found Xkr8 as a complex with basigin (BSG) or ...neuroplastin (NPTN), type I membrane proteins in the Ig superfamily. In BSG−/−NPTN−/−
cells, Xkr8 localized intracellularly, and the apoptosis stimuli failed to expose phosphatidylserine, indicating that BSG and NPTN chaperone Xkr8 to the plasma membrane to execute its scrambling activity. Mutational analyses of BSG showed that the atypical glutamic acid in the transmembrane region is required for BSG’s association with Xkr8. In cells exposed to apoptotic signals, Xkr8 was cleaved at the C terminus and the Xkr8/BSG complex formed a higher-order complex, likely to be a heterotetramer consisting of two molecules of Xkr8 and two molecules of BSG or NPTN, suggesting that this cleavage causes the formation of a larger complex of Xkr8-BSG/NPTN for phospholipid scrambling.
Phosphatidylserine (PtdSer) exposure on the surface of activated platelets requires the action of a phospholipid scramblase(s), and serves as a scaffold for the assembly of the tenase and ...prothrombinase complexes involved in blood coagulation. Here, we found that the activation of mouse platelets with thrombin/collagen or Ca2+ionophore at 20 °C induces PtdSer exposure without compromising plasma membrane integrity. Among five transmembrane protein 16 (TMEM16) members that support Ca2+-dependent phospholipid scrambling, TMEM16F was the only one that showed high expression in mouse platelets. Platelets from platelet-specificTMEM16F-deficient mice exhibited defects in activation-induced PtdSer exposure and microparticle shedding, although α-granule and dense granule release remained intact. The rate of tissue factor-induced thrombin generation byTMEM16F-deficient platelets was severely reduced, whereas thrombin-induced clot retraction was unaffected. The imaging of laser-induced thrombus formation in whole animals showed that PtdSer exposure on aggregated platelets was TMEM16F-dependent in vivo. The phenotypes of the platelet-specificTMEM16F-null mice resemble those of patients with Scott syndrome, a mild bleeding disorder, indicating that these mice may provide a useful model for human Scott syndrome.
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