Cell death

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Overview of signal transduction pathways involved in apoptosis Signal transduction pathways.svg
Overview of signal transduction pathways involved in apoptosis

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. [1]

Contents

Programmed cell death

Programmed cell death (PCD) is cell death mediated by an intracellular program. [2] [3] PCD is carried out in a regulated 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 separate. PCD serves fundamental functions during both plant and metazoa (multicellular animals) tissue development.

Apoptosis

Morphological changes associated with apoptosis Apoptotic cell disassembly.png
Morphological changes associated with apoptosis

Apoptosis is the processor of programmed cell death (PCD) that may occur in multicellular organisms. [3] Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. It is now thought that – in a developmental context – cells are induced to positively commit suicide whilst in a homeostatic context; the absence of certain survival factors may provide the impetus for suicide. There appears to be some variation in the morphology and indeed the biochemistry of these suicide pathways; some treading the path of "apoptosis", others following a more generalized pathway to deletion, but both usually being genetically and synthetically motivated. There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade, however, presumably true apoptosis and programmed cell death must be genetically mediated. It is also becoming clear that mitosis and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors. [4]

Example events in autophagy Autophagy.jpg
Example events in autophagy

Autophagy

Autophagy is cytoplasmic , characterized by the formation of large vacuoles that eat away organelles in a specific sequence prior to the destruction of the nucleus. [5] Macroautophagy, often referred to as autophagy, is a catabolic process that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents, abnormal protein aggregates, and excess or damaged organelles. Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological as well as pathological processes such as development, differentiation, neurodegenerative diseases, stress, infection and cancer.

Other variations of PCD

Other pathways of programmed cell death have been discovered. [6] Called "non-apoptotic programmed cell-death" (or "caspase-independent programmed cell-death"), these alternative routes to death are as efficient as apoptosis and can function as either backup mechanisms or the main type of PCD.

Some such forms of programmed cell death are anoikis, almost identical to apoptosis except in its induction; cornification, a form of cell death exclusive to the eyes; excitotoxicity; ferroptosis, an iron-dependent form of cell death [7] and Wallerian degeneration.

Plant cells undergo particular processes of PCD similar to autophagic cell death. However, some common features of PCD are highly conserved in both plants and metazoa.

Activation-induced cell death (AICD) is a programmed cell death caused by the interaction of Fas receptor (Fas, CD95)and Fas ligand (FasL, CD95 ligand). [8] It occurs as a result of repeated stimulation of specific T-cell receptors (TCR) and it helps to maintain the periphery immune tolerance. [9] Therefore, an alteration of the process may lead to autoimmune diseases. [8] In the other words AICD is the negative regulator of activated T-lymphocytes.

Ischemic cell death, or oncosis, is a form of accidental, or passive cell death that is often considered a lethal injury. The process is characterized by mitochondrial swelling, cytoplasm vacuolization, and swelling of the nucleus and cytoplasm. [10]

Mitotic catastrophe is an oncosuppressive mechanism that can lead to cell death that is due to premature or inappropriate entry of cells into mitosis. [11] It is the most common mode of cell death in cancer cells exposed to ionizing radiation and many other anti-cancer treatments. [12]

Immunogenic cell death or immunogenic apoptosis is a form of cell death caused by some cytostatic agents such as anthracyclines, oxaliplatin and bortezomib, or radiotherapy and photodynamic therapy (PDT). [13]

Pyroptosis is a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response in myeloid cells. [14]

PANoptosis is a unique inflammatory cell death pathway that integrates components from other cell death pathways. The totality of biological effects in PANoptosis cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone. PANoptosis is regulated by multifaceted macromolecular complexes termed PANoptosomes. [15]

Necrotic cell death

Necrosis is cell death where a cell has been badly damaged through external forces such as trauma or infection and occurs in several different forms. In necrosis, a cell undergoes swelling, followed by uncontrolled rupture of the cell membrane with cell contents being expelled. These cell contents often then go on to cause inflammation in nearby cells. [16] 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. Necroptotic pathways are associated with death receptors such as the tumor necrosis factor receptor 1. [16] Identification of cell death was previously classified based on morphology, but in recent years switched to molecular and genetic conditions.

Field of study and etymology

The term "cell necrobiology" has been used to describe the life processes associated with morphological, biochemical, and molecular changes which predispose, precede, and accompany cell death, as well as the consequences and tissue response to cell death. [17] The word is derived from the Greek νεκρό meaning "death", βìο meaning "life", and λόγος meaning "the study of". The term was initially coined to broadly define investigations of the changes that accompany cell death, detected and measured by multiparameter flow- and laser scanning- cytometry. [14] It has been used to describe the real-time changes during cell death, detected by flow cytometry. [18]

See also

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 between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen 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.

Programmed cell death is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers advantage during an organism's lifecycle. 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.

<span class="mw-page-title-main">Autophagy</span> Cellular catabolic process in which cells digest parts of their own cytoplasm

Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.

<span class="mw-page-title-main">Reactive oxygen species</span> Highly reactive molecules formed from diatomic oxygen (O₂)

In chemistry and biology, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (O2), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (O2H), superoxide (O2-), hydroxyl radical (OH.), and singlet oxygen. ROS are pervasive because they are readily produced from O2, which is abundant. ROS are important in many ways, both beneficial and otherwise. ROS function as signals, that turn on and off biological functions. They are intermediates in the redox behavior of O2, which is central to fuel cells. ROS are central to the photodegradation of organic pollutants in the atmosphere. Most often however, ROS are discussed in a biological context, ranging from their effects on aging and their role in causing dangerous genetic mutations.

<span class="mw-page-title-main">TRAIL</span> Mammalian protein

In the field of cell biology, TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death called apoptosis.

<span class="mw-page-title-main">TNF receptor superfamily</span> Protein superfamily of cytokine receptors

The tumor necrosis factor receptor superfamily (TNFRSF) is a protein superfamily of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine-rich domain. With the exception of nerve growth factor (NGF), all TNFs are homologous to the archetypal TNF-alpha. In their active form, the majority of TNF receptors form trimeric complexes in the plasma membrane. Accordingly, most TNF receptors contain transmembrane domains (TMDs), although some can be cleaved into soluble forms, and some lack a TMD entirely. In addition, most TNF receptors require specific adaptor protein such as TRADD, TRAF, RIP and FADD for downstream signalling. TNF receptors are primarily involved in apoptosis and inflammation, but they can also take part in other signal transduction pathways, such as proliferation, survival, and differentiation. TNF receptors are expressed in a wide variety of tissues in mammals, especially in leukocytes.

<span class="mw-page-title-main">Fas receptor</span> Protein found in humans

The Fas receptor, also known as Fas, FasR, apoptosis antigen 1, cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the FAS gene. Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.

<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.

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.

<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 receptor 6</span> Protein found in humans

Death receptor 6 (DR6), also known as tumor necrosis factor receptor superfamily member 21 (TNFRSF21), is a cell surface receptor of the tumor necrosis factor receptor superfamily which activates the JNK and NF-κB pathways. It is mostly expressed in the thymus, spleen and white blood cells. The Gene for DR6 is 78,450 bases long and is found on the 6th chromosome. This is transcribed into a 655 amino acid chain weighing 71.8 kDa. Post transcriptional modifications of this protein include glycosylation on the asparagines at the 82, 141, 252, 257, 278, and 289 amino acid locations.

<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.

Anticancer genes exhibit a preferential ability to kill cancer cells while leaving healthy cells unharmed. This phenomenon is achieved through various processes such as apoptosis following a mitotic catastrophe, necrosis, and autophagy. In the late 1990s, extensive research in the field of cancer cells led to the discovery of anticancer genes. Mutations in these genes due to base substitutions leading to insertions, deletions, or alterations in missense amino acids can cause frameshifts, thereby altering the protein. A change in gene copy number or rearrangements is also essential for deregulating these genes. The loss or alteration of these anticancer genes due to mutations or rearrangements may lead to the development of cancer.

<span class="mw-page-title-main">Necroptosis</span> Programmed form of necrosis, or inflammatory cell death

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. 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.

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.

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.

PANoptosis is a unique, innate immune, inflammatory, and lytic cell death pathway driven by caspases and RIPKs and regulated by multiprotein PANoptosome complexes. The assembly of the PANoptosome cell death complex occurs in response to germline-encoded pattern-recognition receptors (PRRs) sensing pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, and cytokines that are released during infections, inflammatory conditions, and cancer. Several PANoptosome complexes, such as the ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosomes, have been characterized so far.

References

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