Necroptosis

Last updated
The Necroptosis Signaling Pathway Necroptosis Pathway Diagram.png
The Necroptosis Signaling Pathway

Necroptosis is a programmed form of necrosis, or inflammatory cell death. [1] Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. [2] In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction. [3] [4]

Contents

The signaling pathway responsible for carrying out necroptosis is generally understood. TNFα leads to stimulation of its receptor TNFR1. TNFR1 binding protein TNFR-associated death protein TRADD and TNF receptor-associated factor 2 TRAF2 signals to RIPK1 which recruits RIPK3 forming the necrosome also named ripoptosome. [2] Phosphorylation of MLKL by the ripoptosome drives oligomerization of MLKL, allowing MLKL to insert into and permeabilize plasma membranes and organelles. [5] [6] Integration of MLKL leads to the inflammatory phenotype and release of damage-associated molecular patterns (DAMPs), which elicit immune responses.

Function

Necroptosis is specific to vertebrates and may have originated as an additional defense to pathogens. Necroptosis also acts as an alternative "fail-safe" cell death pathway in cases where cells are unable to undergo apoptosis, such as during viral infection in which apoptosis signaling proteins are blocked by the virus.

In innate immunity

Cell suicide is an effective means of stemming the spread of a pathogen throughout an organism. In apoptotic responses to infection, the contents of an infected cell (including the pathogen) are contained and engulfed by phagocytosis. Some pathogens, such as human cytomegalovirus, express caspase inhibitors that arrest the apoptotic machinery of the host cell. [7] The caspase-independence of necroptosis allows the cell to bypass caspase activation, decreasing the time during which the pathogen can inhabit the cell.

Toll-like receptors (TLRs) can also signal to the necrosome, leading to necroptosis. TLRs are a class of receptors that function in the innate immune system to recognize conserved components of pathogens, such as flagellin. [2]

In contrast to apoptosis

In apoptosis, extrinsic signaling via cell surface receptors or intrinsic signaling by release of cytochrome c from mitochondria leads to caspase activation. Proteolytic degradation of the cell's interior culminates with the packaging of the cell's remains into apoptotic bodies, which are degraded and recycled by phagocytosis. Unlike in apoptosis, necrosis and necroptosis do not involve caspase activation. Necrotic cell death culminates in leakage of cell contents into the extracellular space, in contrast to the organized disposal of cellular contents into apoptotic bodies. [8]

Process

As in all forms of necrotic cell death, cells undergoing necroptosis rupture and leak their contents into the intercellular space. Unlike in necrosis, permeabilization of the cell membrane during necroptosis is tightly regulated. While many of these mechanisms and components of the pathway are still being uncovered, the major steps of necroptotic signaling have been outlined in recent years.[ when? ] First, extrinsic stimulus through the TNF receptor by TNFα signals the recruitment of the TNF receptor-associated death domain (TRADD) which in turn recruits RIPK1. In the absence of active Caspase 8, RIPK1 and RIPK3 auto- and transphosphorylate each other, leading to the formation of a microfilament-like complex called the necrosome. [2] The necrosome then activates the pro-necroptotic protein MLKL via phosphorylation. MLKL actuates the necrosis phenotype by inserting into the bilipid membranes of organelles and plasma membrane leading to expulsion of cellular contents into the extracellular space. [5] [6] The inflammatory rupturing of the cell releases Damage Associated Molecular Patterns (DAMPs) into the extracellular space. Many of these DAMPs remain unidentified, however, the "find me" and "eat me" DAMP signals are known to recruit immune cells to the damaged/infected tissue. [8] Necrotic cells are cleared from the immune system by a mechanism called pinocytosis, or cellular drinking, which is mediated by macropinosomes, a subcellular component of macrophages. This process is in contrast to removal of apoptotic cells by the immune system in which cells are removed via phagocytosis, or cellular eating.

Co-regulation of necroptosis and apoptosis

Recent studies have shown substantial interplay between the apoptosis and necroptosis pathways. At multiple stages of their respective signalling cascades, the two pathways can regulate each other. The best characterized example of this co-regulation is the ability of caspase 8 to inhibit the formation of the necrosome by cleaving RIPK1. Conversely, caspase 8 inhibition of necroptosis can be bypassed by the necroptotic machinery through the anti-apoptotic protein cFLIP which inactivates caspase 8 through formation of a heterodimer. [4]

Many components of the two pathways are also shared. The Tumor Necrosis Factor Receptor can signal for both apoptosis and necroptosis. The RIPK1 protein can also signal for both apoptosis and necroptosis depending on post-translational modifications mediated by other signalling proteins. Furthermore, RIPK1 can be regulated by cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1, cIAP2) which polyubiquitinate RIPK1 leading to cell survival through downstream NF-kB signalling. cIAP1 and cIAP2 can also be regulated by the pro-apoptotic protein SMAC (second mitochondria-derived activator of caspases) which can cleave cIAP1 and cIAP2 driving the cell towards an apoptotic death. [2]

Targeting of organelles

Cells can undergo necroptosis in response to perturbed homeostasis in specific circumstances. In response to DNA damage, the RIPK1 and RIPK3 are phosphorylated and lead to deterioration of the cell in the absence of caspase activation. The necrosome inhibits the adenine nucleotide translocase in mitochondria to decrease cellular ATP levels. [8] Uncoupling of the mitochondrial electron transport chain leads to additional mitochondrial damage and opening of the mitochondrial permeability transition pore, which releases mitochondrial proteins into the cytosol. The necrosome also causes leakage of lysosomal digestive enzymes into the cytoplasm by induction of reactive oxygen species by JNK, sphingosine production, and calpain activation by calcium release.

Medical relevance

Necroptosis has been implicated in the pathology of many types of acute tissue damage, including myocardial infarction, stroke, ischemia-reperfusion injury. In addition, necroptosis is noted to contribute to atherosclerosis, pancreatitis, inflammatory bowel disease, neurodegeneration, and some cancers. [9] It has also been implicated in Alzheimer's disease triggered by the production of MEG3 in the brain cells. [10] [11]

In solid-organ transplantation, ischemia-reperfusion injury can occur when blood returns to tissue for the first time in the transplant recipient. A major contributor to tissue damage results from activation of regulated necroptosis, which could include contributions from both necroptosis and mitochondrial permeability transition. Treatment with the drug cyclosporine, which represses the mitochondrial permeability transition effector Cyclophilin D, improves tissue survival primarily by inhibiting necrotic cell death, rather than its additional function as an immunosuppressant. [4]

Necroptosis based-therapy

Recently, necroptosis-based cancer therapy, using a distinctive molecular pathway for regulation of necroptosis, has been suggested as an alternative method to overcome apoptosis-resistance. For instance, necroptotic cells release highly immunogenic DAMPs, initiating adaptive immunity. These dying cells can also activate NF-κB to express cytokines, recruiting macrophages. [12] As of 2018 little is known about negative regulators of necroptosis, but CHIP, cFLIP and FADD appear to be potential targets for necroptosis based therapy. [12]

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses 50 to 70 billion cells each day due to apoptosis. For the average human child between 8 and 14 years old, each day the approximate loss is 20 to 30 billion cells.

<span class="mw-page-title-main">Necrosis</span> Unprogrammed cell death caused by external cell injury

Necrosis is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who is often regarded as one of the founders of modern pathology. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated digestion of cell components. In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death. While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal.

<span class="mw-page-title-main">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

<span class="mw-page-title-main">Cell death</span> Biological cell ceasing to carry out its functions

Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as diseases, localized injury, or the death of the organism of which the cells are part. Apoptosis or Type I cell-death, and autophagy or Type II cell-death are both forms of programmed cell death, while necrosis is a non-physiological process that occurs as a result of infection or injury.

<span class="mw-page-title-main">FADD</span> Human protein and coding gene

FAS-associated death domain protein, also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">Caspase 8</span> Protein-coding gene in the species Homo sapiens

Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds.

Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

<span class="mw-page-title-main">Diablo homolog</span> Protein-coding gene in the species Homo sapiens

Diablo homolog (DIABLO) is a mitochondrial protein that in humans is encoded by the DIABLO gene on chromosome 12. DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC. This protein binds inhibitor of apoptosis proteins (IAPs), thus freeing caspases to activate apoptosis. Due to its proapoptotic function, SMAC is implicated in a broad spectrum of tumors, and small molecule SMAC mimetics have been developed to enhance current cancer treatments.

<span class="mw-page-title-main">RIPK1</span> Enzyme found in humans

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis and necroptosis. Some of the cell survival pathways RIPK1 participates in include NF-κB, Akt, and JNK.

<span class="mw-page-title-main">Death domain</span>

The death domain (DD) is a protein interaction module composed of a bundle of six alpha-helices. DD is a subclass of protein motif known as the death fold and is related in sequence and structure to the death effector domain (DED) and the caspase recruitment domain (CARD), which work in similar pathways and show similar interaction properties. DD bind each other forming oligomers. Mammals have numerous and diverse DD-containing proteins. Within these proteins, the DD domains can be found in combination with other domains, including: CARDs, DEDs, ankyrin repeats, caspase-like folds, kinase domains, leucine zippers, leucine-rich repeats (LRR), TIR domains, and ZU5 domains.

Safingol is a lyso-sphingolipid protein kinase inhibitor. It has the molecular formula C18H39NO2 and is a colorless solid. Medicinally, safingol has demonstrated promising anticancer potential as a modulator of multi-drug resistance and as an inducer of necrosis. The administration of safingol alone has not been shown to exert a significant effect on tumor cell growth. However, preclinical and clinical studies have shown that combining safingol with conventional chemotherapy agents such as fenretinide, vinblastine, irinotecan and mitomycin C can dramatically potentiate their antitumor effects. In phase I clinical trials, it was found to be safe to co-administer with cisplatin, but caused reversible dose-dependent hepatotoxicity.

Ischemic cell death, or oncosis, is a form of accidental cell death. The process is characterized by an ATP depletion within the cell leading to impairment of ionic pumps, cell swelling, clearing of the cytosol, dilation of the endoplasmic reticulum and golgi apparatus, mitochondrial condensation, chromatin clumping, and cytoplasmic bleb formation. Oncosis refers to a series of cellular reactions following injury that precedes cell death. The process of oncosis is divided into three stages. First, the cell becomes committed to oncosis as a result of damage incurred to the plasma membrane through toxicity or ischemia, resulting in the leak of ions and water due to ATP depletion. The ionic imbalance that occurs subsequently causes the cell to swell without a concurrent change in membrane permeability to reverse the swelling. In stage two, the reversibility threshold for the cell is passed and the cell becomes committed to cell death. During this stage the membrane becomes abnormally permeable to trypan blue and propidium iodide, indicating membrane compromise. The final stage is cell death and removal of the cell via phagocytosis mediated by an inflammatory response.

Apoptotic-cell associated molecular patterns (ACAMPs) are molecular markers present on cells which are going through apoptosis, i.e. programmed cell death. The term was used for the first time by C. D. Gregory in 2000. Recognition of these patterns by the pattern recognition receptors (PRRs) of phagocytes then leads to phagocytosis of the apoptotic cell. These patterns include eat-me signals on the apoptotic cells, loss of don’t-eat-me signals on viable cells and come-get-me signals ) secreted by the apoptotic cells in order to attract phagocytes. Thanks to these markers, apoptotic cells, unlike necrotic cells, do not trigger the unwanted immune response.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

<span class="mw-page-title-main">Paraptosis</span> Type of programmed cell death distinct from apoptosis and necrosis

Paraptosis is a type of programmed cell death, morphologically distinct from apoptosis and necrosis. The defining features of paraptosis are cytoplasmic vacuolation, independent of caspase activation and inhibition, and lack of apoptotic morphology. Paraptosis lacks several of the hallmark characteristics of apoptosis, such as membrane blebbing, chromatin condensation, and nuclear fragmentation. Like apoptosis and other types of programmed cell death, the cell is involved in causing its own death, and gene expression is required. This is in contrast to necrosis, which is non-programmed cell death that results from injury to the cell.

Junying Yuan is the Elizabeth D. Hay Professor of Cell Biology at Harvard Medical School, best known for her work in cell death. Early in her career, she contributed significant findings to the discovery and characterization of apoptosis. More recently, she was responsible for the discovery of the programmed form of necrotic cell death known as necroptosis.

cIAP1 is the abbreviation for a human protein, cellular inhibitor of apoptosis protein-1. It belongs to the IAP family of proteins and therefore contains at least one BIR domain. cIAP1 is a multi-functional protein which can be found in the cytoplasm of cells and in the nucleus of tumor cells. Its function in this particular case is yet to be understood. However, it is well known that this protein has a big influence in the growth of diverse cancers. cIAP1 is involved in the development process of osteosarcoma and gastric cancer among others.

<span class="mw-page-title-main">Vishva Dixit</span> Kenyan molecular biologist

Vishva Mitra Dixit is a physician of Indian origin who is the current Vice President of Discovery Research at Genentech.

References

  1. ↑ Nirmala JG, Lopus M (April 2020). "Cell death mechanisms in eukaryotes". Cell Biology and Toxicology. 36 (2): 145–164. doi:10.1007/s10565-019-09496-2. PMID   31820165. S2CID   208869679.
  2. 1 2 3 4 5 Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P (February 2014). "Regulated necrosis: the expanding network of non-apoptotic cell death pathways". Nature Reviews. Molecular Cell Biology. 15 (2): 135–47. doi:10.1038/nrm3737. PMID   24452471. S2CID   13919892.
  3. ↑ Günther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF, Becker C (September 2011). "Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis". Nature. 477 (7364): 335–9. Bibcode:2011Natur.477..335G. doi:10.1038/nature10400. PMC   3373730 . PMID   21921917.
  4. 1 2 3 Linkermann A, Green DR (January 2014). "Necroptosis". The New England Journal of Medicine. 370 (5): 455–65. doi:10.1056/nejmra1310050. PMC   4035222 . PMID   24476434.
  5. 1 2 Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS, Wang X (April 2014). "Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3". Molecular Cell. 54 (1): 133–146. doi: 10.1016/j.molcel.2014.03.003 . PMID   24703947.
  6. 1 2 Su L, Quade B, Wang H, Sun L, Wang X, Rizo J (October 2014). "A plug release mechanism for membrane permeation by MLKL". Structure. 22 (10): 1489–500. doi:10.1016/j.str.2014.07.014. PMC   4192069 . PMID   25220470.
  7. ↑ Mocarski ES, Upton JW, Kaiser WJ (December 2011). "Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways". Nature Reviews. Immunology. 12 (2): 79–88. doi:10.1038/nri3131. PMC   4515451 . PMID   22193709.
  8. 1 2 3 Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (October 2010). "Molecular mechanisms of necroptosis: an ordered cellular explosion". Nature Reviews. Molecular Cell Biology. 11 (10): 700–14. doi: 10.1038/nrm2970 . PMID   20823910. S2CID   7424865.
  9. ↑ Zhou W, Yuan J (November 2014). "Necroptosis in health and diseases". Seminars in Cell & Developmental Biology. 35: 14–23. doi: 10.1016/j.semcdb.2014.07.013 . PMID   25087983.
  10. ↑ Balusu S, Horré K, Thrupp N, Craessaerts K, Snellinx A, Serneels L, T'Syen D, Chrysidou I, Arranz AM, Sierksma A, Simrén J, Karikari TK, Zetterberg H, Chen WT, Thal DR, Salta E, Fiers M, De Strooper B. MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease. Science. 2023 Sep 15;381(6663):1176-1182. doi : 10.1126/science.abp9556 PMID   37708272
  11. ↑ "Scientists discover how brain cells die in Alzheimer's". BBC News. 2023-09-15. Retrieved 2023-09-27.
  12. 1 2 Razaghi A, Heimann K, Schaeffer PM, Gibson SB (January 2018). "Negative regulators of cell death pathways in cancer: perspective on biomarkers and targeted therapies". Apoptosis. 23 (2): 93–112. doi:10.1007/s10495-018-1440-4. PMID   29322476. S2CID   3424489.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.