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Cell death

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发布日期: 2024年3月29日

Cell death is an essential mechanism for maintaining morphogenesis and physiological homeostasis during development by eliminating damaged, senescent, or harmful cells. It also serves to reduce the spread of pathogens by eliminating infected cells. Programmed Cell Death (PCD) encompasses various cellular death processes, including apoptosis, necroptosis, pyroptosis, ferroptosis, as well as cell death processes associated with autophagy and non-programmed necrosis.

Cell death can be non-lytic, characterized by immunologically silent apoptosis, or lytic and pro-inflammatory necrosis. In multicellular organisms, genetically programmed cell death is a crucial mechanism for maintaining physiological balance. Single-celled organisms also utilize cell death to resist pathogen invasion or limit population size in response to nutrient scarcity.

Recently, a paper?on cell death published in Cell has attracted much attention. The authors explore the role of PCD in a variety of common diseases and discuss the interplay between different cell death signaling cascades and disease pathogenesis.

?Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01332-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867423013326%3Fshowall%3Dtrue#secsectitle0010

Intrinsic?apoptosis - From worms?to mammals

The article starts by introducing the topic through the elegans, Caenorhabditis elegans, known for its studies on apoptosis, elaborating on the intrinsic apoptotic pathways and the key cellular factors involved in this process. Further, it compares the intrinsic apoptotic signaling pathways in mammals with those in C. elegans and fruit flies.

The similarities lie in their utilization of scaffold proteins to coordinate the activation of caspases, thereby inducing apoptosis. In C. elegans, CED-4 fulfills this function, responsible for activating the caspase CED-3. In mammals, it is mediated by apoptotic protease-activating factor 1 (Apaf-1), which facilitates the aggregation of caspase-9.

2. Extrinsic apoptosis and necroptosis

Extrinsic apoptosis and necroptosis pathways are primarily initiated by the binding of death receptors to their ligands. This process transmits apoptotic signals via caspase-8. When caspase-8 is inhibited, necroptosis may occur, which is a form of lytic cell death.

Necroptosis may have evolved as an antiviral defense mechanism, as some viruses can encode proteins that inhibit caspase-8 to prevent apoptosis. Similar to caspase-9 in the intrinsic apoptosis pathway, caspase-8 executes the apoptosis program by cleaving and activating caspase-3 and caspase-7.

In the mechanisms of extrinsic apoptosis or necroptosis, ligand-receptor pairings include FAS ligand (FASL) with FAS, tumor necrosis factor (TNF) or lymphotoxin-α with TNF receptor 1 (TNFR1), TNF-like cytokine 1A (TL1A) with death receptor 3 (DR3), and inducible apoptosis ligand (TRAIL) with TRAIL receptors 1 or 2 (TRAILR1 or TRAILR2).

In addition to death receptors, the mechanisms of extrinsic apoptosis or necroptosis can also be activated through Toll-like receptor 3 (TLR3), TLR4, or Z-DNA binding protein 1 (ZBP1). (As shown in the diagram below.)

3. Induction of GSDMD-dependent pyroptosis by inflammasome activation

Pyroptosis is a form of cell death triggered by the formation of gasdermin pores on the cytoplasmic membrane, representing a unique cellular demise mechanism discovered in studies of macrophages infected with Salmonella. This type of cell death in infected macrophages relies on the activation of caspase-1, which cleaves gasdermin D (GSDMD) to induce pyroptosis, alongside the proteolytic maturation of IL-18 and the endogenous pyrogenic factor IL-1β.

Inflammasomes are multiprotein complexes formed by the dimerization of caspase-1 in the cytoplasm. These complexes respond to specific damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), assembling into oligomeric scaffolds, as illustrated in the diagram below.

4. Ferroptosis

Ferroptosis?is a form of non-apoptotic cell death triggered by the accumulation of lethal levels of iron-dependent lipid peroxides. Cells undergoing ferroptosis?rupture, but the mechanism by which lipid peroxides disrupt membrane integrity remains unclear.

Key factors contributing to the susceptibility of cells to iron death include metabolic enzymes involved in the synthesis of easily oxidizable membrane lipids, such as members of the acyl-CoA synthetase family 4 (ASCL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), as well as iron-dependent enzymes involved in lipid oxidation, such as arachidonate lipoxygenase (as illustrated below).