Necroptosis

Necroptosis is a programmed form of necrosis, or inflammatory cell death. 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.[1] 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.[2][3]

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.[1] Phosphorylation of MLKL by the ripoptosome drives oligomerization of MLKL, allowing MLKL to insert into and permeabilize plasma membranes and organelles.[4][5] Integration of MLKL leads to the inflammatory phenotype and release of damage-associated molecular patterns (DAMPs), which elicit immune responses.

Necroptosis Pathway Diagram
The Necroptosis Signaling Pathway

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.[6] 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.[1]

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.[7]

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. 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.[1] 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.[4][5] 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.[7] 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.[3]

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.[1]

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.[7] 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 myocardinal infarction, stroke, ischemia-reperfusion injury. In addition, necroptosis is noted to contribute to atherosclerosis, pancreatitis, inflammatory bowel disease, neurodegeneration, and some cancers.[8]

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.[3]

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.[9] 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.[9]

References

  1. ^ a b c d e 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.
  2. ^ 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. doi:10.1038/nature10400. PMC 3373730. PMID 21921917.
  3. ^ a b c 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.
  4. ^ a b 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.
  5. ^ a b 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.
  6. ^ 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.
  7. ^ a b c 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.
  8. ^ 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.
  9. ^ a b 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: 1–20. doi:10.1007/s10495-018-1440-4. PMID 29322476.
Caspase

Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death (including apoptosis, pyroptosis and necroptosis) and inflammation. 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 11 or 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

The role of these enzymes in programmed cell death was first identified in 1993, with their functions in apoptosis well characterised. This is a form of programmed cell death, occurring widely during development, and throughout life to maintain cell homeostasis. Activation of caspases ensures that the cellular components are degraded in a controlled manner, carrying out cell death with minimal effect on surrounding tissues.Caspases have other identified roles in programmed cell death such as pyroptosis and necroptosis. These forms of cell death are important for protecting an organism from stress signals and pathogenic attack. Caspases also have a role in inflammation, whereby it directly processes pro-inflammatory cytokines such as pro-IL1β. These are signalling molecules that allow recruitment of immune cells to an infected cell or tissue. There are other identified roles of caspases such as cell proliferation, tumour suppression, cell differentiation, neural development and axon guidance and ageing.Caspase deficiency has been identified as a cause of tumour development. Tumour growth can occur by a combination of factors, including a mutation in a cell cycle gene which removes the restraints on cell growth, combined with mutations in apoptopic proteins such as Caspases that would respond by inducing cell death in abnormally growing cells. Conversely, over-activation of some caspases such as caspase-3 can lead to excessive programmed cell death. This is seen in several neurodegenerative diseases where neural cells are lost, such as Alzheimer's disease. Caspases involved with processing inflammatory signals are also implicated in disease. Insufficient activation of these caspases can increase an organism's susceptibility to infection, as an appropriate immune response may not be activated. The integral role caspases play in cell death and disease has led to research on using caspases as a drug target. For example, inflammatory caspase-1 has been implicated in causing autoimmune diseases; drugs blocking the activation of Caspase-1 have been used to improve the health of patients. Additionally, scientists have used caspases as cancer therapy to kill unwanted cells in tumours.

Cell death

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, or may result from such factors as disease, 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.

Dead on arrival

Dead on arrival (DOA), also dead in the field and brought in dead (BID), indicates that a patient was found to be already clinically dead upon the arrival of professional medical assistance, often in the form of first responders such as emergency medical technicians, paramedics, or police.

In some jurisdictions, first responders must consult verbally with a physician before officially pronouncing a patient deceased, but once cardiopulmonary resuscitation is initiated, it must be continued until a physician can pronounce the patient dead.

Death domain

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.Some DD-containing proteins are involved in the regulation of apoptosis and inflammation through their activation of caspases and NF-κB, which typically involves interactions with TNF (tumour necrosis factor) cytokine receptors. In humans, eight of the over 30 known TNF receptors contain DD in their cytoplasmic tails; several of these TNF receptors use caspase activation as a signaling mechanism. The DD mediates self-association of these receptors, thus giving the signal to downstream events that lead to apoptosis. Other DD-containing proteins, such as ankyrin, MyD88 and pelle, are probably not directly involved in cell death signalling. DD-containing proteins also have links to innate immunity, communicating with Toll-like receptors through bipartite adapter proteins such as MyD88.The DD superfamily is one of the largest and most studied domain superfamilies. It currently comprises four subfamilies, the death domain (DD) subfamily, the death effector domain (DED) subfamily, the caspase recruitment domain (CARD) subfamily and the pyrin domain (PYD) subfamily. These proteins are evolutionarily conserved in many multicellular organisms such as mammals, Drosophila and C. elegans.

Based on a genome analysis, there are 32 DDs, 7 DEDs, 28 CARDs and 19 PYDs in the human genome.Due to the large size of the death domain family protein superfamily, some death domain proteins may have a role to play in cancer and many other infections through several families of DD-proteins and specific gene alterations that have a downstream function to induce cell apoptosis. Many of these alterations occur in genes encoding mediators of apoptosis or necroptosis, potentially enabling the development of resistance to cell death, an important hallmark of cancer. Many cancers contain an oncogene that will inhibit the MHC complex on the cell surface from presenting antigens to immune cells. Many of these malignancies have a subset of cases harboring genomic alterations in components of intrinsic or extrinsic cell death pathways, including amplification and overexpression of the Fas-associated via death domain (FADD) and inhibitor of apoptosis proteins (IAP), as well as mutations in caspase-encoding genes. One example of this can be seen in head and neck squamous cell carcinomas. (HNSCC) Head and neck squamous cell carcinomas are among the cancers with the highest frequency of deregulation in genes encoding for cell death pathway constituents, with nearly half of all cases exhibiting such genomic alterations.In addition to cancer, deregulation of death receptor protein signaling and death domain recruitment is seen to influence many other human diseases. Notably, the Fas death domain can have mutations that lead to Autoimmune lymphoproliferative syndrome, lung cancer, and squamous cell carcinoma. The defective in Fas signaling can lead to a disruption in the function of the death inducing signaling complex (DISC).

Specifically, in ALPS, cell apoptosis that occurs via the CD95 pathway, a transmembrane protein, is found to be vital in controlling the proliferation of activated lymphocytes and regulates lymphocyte homeostasis. Notably, two-point mutation that occur at the A1009G, E256G sites, can cause a defect in apoptotic pathways with people who have ALPS. (Peters,1999) Most patients with ALPS have mutations in the Fas gene and more than 70 mutations have been mapped to its intracellular DD.

Death effector domain

The death-effector domain (DED) is a protein interaction domain found only in eukaryotes that regulates a variety of cellular signalling pathways. The DED domain is found in inactive procaspases (cysteine proteases) and proteins that regulate caspase activation in the apoptosis cascade such as FAS-associating death domain-containing protein (FADD). FADD recruits procaspase 8 and procaspase 10 into a death induced signaling complex (DISC). This recruitment is mediated by a homotypic interaction between the procaspase DED and a second DED that is death effector domain in an adaptor protein that is directly associated with activated TNF receptors. Complex formation allows proteolytic activation of procaspase into the active caspase form which results in the initiation of apoptosis (cell death). Structurally the DED domain are a subclass of protein motif known as the death fold and contains 6 alpha helices, that closely resemble the structure of the Death domain(DD)

Death messenger

Death messengers, in former times, were those who were dispatched to spread the news that an inhabitant of their city or village had died. They were to wear unadorned black and go door to door with the message, "You are asked to attend the funeral of the departed __________ at (time, date, and place)." This was all they were allowed to say, and were to move on to the next house immediately after uttering the announcement. This tradition persisted in some areas to as late as the mid-19th century.

Death rattle

Terminal respiratory secretions (or simply terminal secretions), known colloquially as a death rattle, are sounds often produced by someone who is near death as a result of fluids such as saliva and bronchial secretions accumulating in the throat and upper chest. Those who are dying may lose their ability to swallow and may have increased production of bronchial secretions, resulting in such an accumulation. Usually, two or three days earlier, the symptoms of approaching death can be observed as saliva accumulates in the throat, making it very difficult to take even a spoonful of water. Related symptoms can include shortness of breath and rapid chest movement. While death rattle is a strong indication that someone is near death, it can also be produced by other problems that cause interference with the swallowing reflex, such as brain injuries.It is sometimes misinterpreted as the sound of the person choking to death, or alternatively, that they are gargling.

Dignified death

Dignified death is a somewhat elusive concept often related to suicide. One factor that has been cited as a core component of dignified death is maintaining a sense of control. Another view is that a truly dignified death is an extension of a dignified life. There is some concern that assisted suicide does not guarantee a dignified death, since some patients may experience complications such as nausea and vomiting. There is some concern that age discrimination denies the elderly a dignified death.

FADD

Fas-associated protein with death domain (FADD), also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans.FADD is an adaptor protein that bridges members of the tumor necrosis factor receptor superfamily, such as the Fas-receptor, to procaspases 8 and 10 to form the death-inducing signaling complex (DISC) during apoptosis. As well as its most well known role in apoptosis, FADD has also been seen to play a role in other processes including proliferation, cell cycle regulation and development.

Junying Yuan

Junying Yuan (Chinese: 袁钧瑛; pinyin: Yuán Jūnyīng, born October 3, 1958) 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.

Lazarus sign

The Lazarus sign or Lazarus reflex is a reflex movement in brain-dead or brainstem failure patients, which causes them to briefly raise their arms and drop them crossed on their chests (in a position similar to some Egyptian mummies). The phenomenon is named after the Biblical figure Lazarus of Bethany, whom Jesus Christ raised from the dead in the Gospel of John.

Megadeath

Megadeath (or megacorpse) is one million human deaths, usually caused by a nuclear explosion. The term was used by scientists and thinkers who strategized likely outcomes of all-out nuclear warfare.

Mixed lineage kinase domain like pseudokinase

Mixed lineage kinase domain like pseudokinase (MLKL) is a protein that in humans is encoded by the MLKL gene.

Necronym

A necronym (from the Greek words νεκρός, nekros, "dead" and ὄνομα ónoma, "name") is a reference to, or name of, a person who has died. Many cultures have taboos and traditions associated with referring to such a person. These vary from the extreme of never again speaking the person's real name, often using some circumlocution instead, to the opposite extreme of commemorating it incessantly by naming other things or people after the deceased.

For instance, in some cultures it is common for a newborn child to receive the name (a necronym) of a relative who has recently died, while in others to reuse such a name would be considered extremely inappropriate or even forbidden. While this varies from culture to culture, the use of necronyms is quite common.

Obituary

An obituary (obit for short) is a news article that reports the recent death of a person, typically along with an account of the person's life and information about the upcoming funeral. In large cities and larger newspapers, obituaries are written only for people considered significant. In local newspapers, an obituary may be published for any local resident upon death. A necrology is a register or list of records of the deaths of people related to a particular organization, group or field, which may only contain the sparsest details, or small obituaries. Historical necrologies can be important sources of information.

Two types of paid advertisements are related to obituaries. One, known as a death notice, omits most biographical details and may be a legally required public notice under some circumstances. The other type, a paid memorial advertisement, is usually written by family members or friends, perhaps with assistance from a funeral home. Both types of paid advertisements are usually run as classified advertisements.

Pallor mortis

Pallor mortis (Latin: pallor "paleness", mortis "of death"), the first stage of death, is an after-death paleness that occurs in those with light/white skin.

Post-mortem interval

Post-mortem interval (PMI) is the time that has elapsed since a person has died. If the time in question is not known, a number of medical/scientific techniques are used to determine it. This also can refer to the stage of decomposition of the body.

Programmed cell death

Programmed cell death (or PCD) is the death of a cell in any form, mediated by an intracellular program, and is also referred to as Cellular Suicide. PCD is carried out in a biological process, which usually confers advantage during an organism's life-cycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and animal tissue development.

Apoptosis and autophagy, both are the forms of programmed cell death, but necrosis was long seen as a non-physiological process that occurs as a result of infection or injury.Necrosis is the death of a cell caused by external factors such as trauma or infection and occurs in several different forms. Recently a form of programmed necrosis, called necroptosis, has been recognized as an alternative form of programmed cell death. It is hypothesized that necroptosis can serve as a cell-death backup to apoptosis when the apoptosis signaling is blocked by endogenous or exogenous factors such as viruses or mutations. Most recently, other types of regulated necrosis have been discovered as well, which share several signaling events with necroptosis and apoptosis.

RIPK1

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an enzyme that in humans is encoded by the RIPK1 gene, which is located on chromosome 6. This protein belongs to the Receptor Interacting Protein (RIP) kinases family, which consists of 7 members, RIPK1 being the first member of the family.RIPK1 is known to have function 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.

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