An Overview of Cell Death Types (III)
Posted by beauty33 on January 1st, 2021
Non-classical pyrolysis pathway, usually LPS directly activates Caspase-4, Caspase-5 and Caspase-11 to mediate pyrolysis. Caspase-4, Caspase-5 and Caspase-11 can be directly stimulated by intracellular gram-negative bacteria LPS , To activate and hydrolyze its own protease activity. Activated Caspase-4, Caspase-5 and Caspase-11 can also act on GSDMD and produce the same lysis effect as Caspase-1, resulting in cell membrane perforation. Activated Caspase-4, Caspase-5 and Caspase-11 can interact with Caspase-1 in the presence of NLRP3 and ASC to promote its activation. The same Caspase-1 cleaves the precursors of IL-1β and IL-18 to form active IL-1β and IL-18, which are released through the membrane channel formed by GSDMD-NT and cause pyrolysis. Unlike the classical pathway, in non-classical pyrolysis, only the cleavage of IL-1β and IL-18 precursors depends on Caspase-1, and the cleavage of GSDMD is completed by other activated inflammatory Caspases.
Ferroptosis is a new method of cell death different from autophagy, apoptosis and necrosis, and is closely related to various human diseases. Iron death is related to the abnormality of intracellular iron and lipid reactive oxygen species, and is caused by iron-dependent lipid peroxide accumulation. Iron death is different from cell death such as necrosis, apoptosis and autophagy. In terms of morphology, iron death has no autophagy lysosome formation. The main accumulated organelle is mitochondria, which is manifested as mitochondrial volume reduction, membrane density increase, and mitochondria reduction of cristae; the mechanism does not depend on the Caspase family, and is mainly regulated by genes such as RPL8, IREB2, ATP5G3, CS, TTC35 and ACSF; in terms of inhibitors, iron death can be inhibited by iron chelator and antioxidants. But it cannot be inhibited by classic apoptosis or autophagy inhibitors.
It is currently believed that the occurrence of iron death is related to the level of intracellular iron metabolism, lipid peroxide content and glutathione peroxidase 4 (GPX4) activity.
Iron and its derivatives are involved in many aspects of cell metabolism. Abnormally increased iron content in the cytoplasm will often lead to excessive divalent iron ions participating in the Fenton reaction to generate hydroxyl free radicals. If the antioxidant capacity of the cells is insufficient to remove excess hydroxyl radical will cause the accumulation of peroxides in cells to induce iron death. The iron chelator deferoxamine can prevent iron death from occurring. In the periphery, transferrin (TF) has a high affinity for ferric iron (Fe3+), and one TF molecule can transport two Fe3+. TF transports Fe3+ to the transferrin receptor 1 (TFR1) of the cell membrane, and then forms a TF-[Fe3+]2-TFR1 complex on the surface of the cell membrane. In addition, iron regulatory protein, hypoxia-inducible factor and RAS genes can up-regulate the expression of TFR1 on the surface of tumor cell membranes and increase iron uptake. Subsequently, the TF-[Fe3+]2-TFR1 complex enters the cell lysosome and releases Fe3+ under lysosomal acidic conditions. Fe3+ is converted into Fe2+ under the action of the iron reductase STEAP3, and is finally released into the cytoplasm to induce cells Iron death occurred. Excess iron is stored in ferritin or is oxidized to Fe3+ by ferroportin on the cell membrane and then transported outside the cell. The iron stored in ferritin can be released into the cytoplasm through the nuclear receptor co-activator 4 (NCOA4) mediating iron autophagy. The iron transport protein in the body is negatively regulated by hepcidin, and the level of hepcidin increases significantly, inhibiting iron efflux. In short, regulating the uptake, storage and efflux of cellular iron is the key to regulating iron death.
Polyunsaturated fatty acids (PUFAs) are an important component of the phospholipid bilayer of the cell membrane and play an important role in maintaining the fluidity of the cell membrane. However, too much PUFAs promote iron death. The main mechanism is that Fe2+ will be excessive through Fenton reaction PUFAs are oxidized to hydroxyl free radicals. These groups also oxidize PUFAs in a chain reaction, producing large amounts of lipid peroxides, and inducing iron death of cells. Current research shows that the fatty acids that make up cell membrane phospholipids play an important role in iron death. Long-chain "acyl-CoA" synthetase 4 (ACSL4) can activate arachidonic acid (AA) and adrenal acid (AdA) into arachidonic acid (AA) and adrenal CoA (AA-CoA) and adrenal CoA (AdA), respectively. Phosphatidylcholine acyltransferase 3 (LPCAT3) binds them to cell membrane phospholipids. The long-chain PUFAs on the membrane phospholipids can often be oxidized to lipid peroxides, thereby triggering cell iron death. In addition, lipoxygenase (LOXs) promotes the oxidation of PUFAs and up-regulates iron death. In short, the accumulation of lipid peroxides is a prerequisite for iron death.
The cystine-glutamate exchange transporter System Xc- of GPX4 located on the cell membrane is a dimer formed by disulfide bonds between light chain subunits (xCT, SLC7A11) and heavy chain subunits (CD98hc, SLC3A2). System Xc- can transport intracellular glutamate to the outside of the cell, transport extracellular cystine into the cell, and convert the intracellular cystine into cysteine to synthesize glutamate that protects the cell from oxidative damage Glutathione (GSH) prevents excessive accumulation of lipid peroxides in cells. Elastin can inhibit the biological activity of Syster Xc- and induce iron death in cells. SLC7A11 expression is up-regulated in many tumor cells, inhibiting iron death of tumor cells. GPX4 is a kind of Selene-protein, GSH is its important cofactor, System Xc- participates in the synthesis of GPX4, and GPX4 can reduce lipid peroxides to corresponding lipid alcohols and inhibit the occurrence of lipid peroxidation.
2 Unprogrammed death
Necrosis is a typical way of unprogrammed cell death. It is cell death induced by extreme physical, chemical, or other serious pathological factors. It is pathological cell death. The membrane permeability of necrotic cells is increased, resulting in cell swelling, deformation or enlargement of organelles, no obvious morphological changes in the early nucleus, and finally cell rupture. The lysis of necrotic cells releases the contents and causes an inflammatory reaction; during the healing process, it is often accompanied by fibrosis of tissues and organs, and scars are formed. Academia has long believed that cell necrosis is a passive process. However, recent studies have also suggested that some proteins are involved in the signal regulation of cell necrosis. Receptor-interacting serine-threonine protein kinase -3 (RIP3) may be a key protein that determines TNF-induced cell necrosis. Under normal circumstances. RIP3, RIP1, and mixed lineage kinase domain-like protein (MLKL) together form the initial necrosome initiation. Under the induction of TNF, RIP3 phosphorylates the 357 threonine and 358 serine of MLKL, which forms the activation of necrosome activation and further mediates cell necrosis. However, the latest research shows that cell necrosis is also programmed, so it is also called necroptosis.
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Joined: July 10th, 2017
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