Programmed cell death

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Programmed cell death is the physiological death of cells in a multicellular organism. This is usually used to specifically remove cells that are unnecessary or obstructive for the development or continued existence of the organism.

The opposite of programmed cell death is the traumatic death of a cell ( necrosis ).

Overview

The programmed death of cells, like their growth ( cell proliferation ), is essential for the self-regulation of a multicellular organism. A failure or a reduction in programmed cell death can lead to tumor formation. An increased cell death rate can also have negative effects, e.g. B. through the development of degenerative diseases such as Huntington's disease or amyotrophic lateral sclerosis .

Programmed cell death plays an important role in the immune system in particular . Cytotoxic T cells eliminate virus-infected or degenerate cells by inducing programmed cell death. Also with the maturation of T-lymphocytes and B-lymphocytes , potentially autoreactive cells, i.e. H. Cells that would attack the body's own tissue are eliminated through programmed cell death. Errors that occur during this process can lead to autoimmune diseases such as multiple sclerosis or rheumatoid arthritis . In addition, after a successful immune response, activated T cells that are no longer needed are removed by programmed cell death.

Programmed cell death was first described in 1842 when observing the ontogeny of vertebrates . Carl Vogt observed that during the development of amphibians, unwanted tissues, such as tails or webbed feet, are specifically broken down through cell death. This “normal” cell death was soon also detected in the ontogenesis of other vertebrates and in invertebrates ( Invertebrata ). The often used term apoptosis was introduced in 1972 and was intended to differentiate natural cell death during ontogenesis from necrosis .

Types of programmed cell death

The International Nomenclature Committee on Cell Death (NCCD) carried out a paradigm shift in 2012: the morphological attempts at definition that had been common up until then caused problems because cells can look similar despite different programs, and technical advances made it possible to gain ever better insights into biochemistry dying cells. Therefore, there was a switch to molecular definitions. In the following, the NCCD definitions of the main types of death are presented first, followed by the committee’s proposed definitions for special cases.

Main types

Extrinsic apoptosis

This cell death program is triggered either by extracellular stress messengers that bind to specific death receptors in the cell membrane, or by the loss of life support signals that are perceived by other receptors. All death receptors have an 80 amino acid long death domain on their inside (in the cytoplasm), which is activated by a conformational change of the receptor when the death signal is bound and triggers a signal chain in the cell, which ultimately leads to death and the orderly disposal of the cell.

Caspases are involved in this signal chain, enzymes typical of apoptosis that cut other proteins behind a certain amino acid. In some cells, the outer of the two mitochondrial membranes is perforated, so that the mitochondria become inoperable and at the same time release toxic proteins into the cytoplasm. Among these, cytochrome c plays a special role: In the cytoplasm, it triggers the formation of a complex made up of many proteins, the apoptosome , which in turn activates caspases that break down the proteins in the cell. In other cells, such as lymphocytes , the caspases that cause cell death are activated without first destroying the outer mitochondrial membrane.

Caspases are also involved in apoptosis, which is not triggered by the binding of death signals but by the loss of life support signals.

Intrinsic apoptosis

This program is triggered by intracellular stress signals such as DNA damage, oxidative stress or the accumulation of misfolded proteins. At the same time as these pro-apoptotic signal cascades that promote the death program, competing anti-apoptotic, that is life-sustaining processes are often started, which are intended to eliminate cell stress in a non-fatal way. The signals converge in the mitochondria and are offset there: If the death signals predominate, the outer mitochondrial membrane is perforated so that the cell runs out of energy, toxic substances from the mitochondria get into the cytoplasm and reactive oxygen species (ROS) accumulate, which in turn amplify the pro-apoptotic signals.

As in extrinsic apoptosis, this is followed by the formation of an apoptosome and the activation of caspases. Other enzymes cut the DNA strands in the cell nucleus. So some of the processes are caspase-dependent, some not. Therefore, this type of cell death cannot be stopped by caspase-inhibiting agents, but only delayed a little.

Necroptosis

The longest and currently best known form of regulated necrosis : Necrosis, conventionally understood as traumatic cell death, can also take place in a regulated manner. Certain DNA damage or the binding of external death signals such as tumor necrosis factor α to death receptors are triggers . Cell death as a result of the described stimuli can occur even without the caspase system. This is mediated via the enzymes RIP1, RIP3 and MLKL. RIP stands for "receptor interacting protein kinase" and MLKL for "mixed linear kinase like pseudokinase". Exactly which processes damage the cell after activation of MLKL is the subject of current research.

Autophagic cell death

In adult organisms, cell death and autophagy - a program to save cells by recycling non-vital structures, for example in deficiency situations - are mostly opposing, blocking programs. During the development of an organism, however, autophagy often ends with the death of the cell; then it can be seen as a form of programmed cell death.

Mitotic catastrophe

If irreparable errors occur during cell nucleus division or mitosis , a program is started to prevent the formation of cell clones with incomplete or incorrectly organized sets of chromosomes, which can turn into tumors. The program results in either death or senescence of the cell .

special cases

Anoikis

A German equivalent for this expression, which means "unhoused", has not yet been established. Many cells in our skin, for example, need contact with an extracellular matrix and the survival signals it emits (e.g. integrin and epidermal growth factor ) in order to thrive. If they lose contact, they go in. The execution of this program is similar to intrinsic apoptosis.

Entosis

Also for the death by consumption by a non-phagocyte, which is mainly observed in tumors, a Germanization is still missing. According to the NCCD, three conditions must be met: 1. The intertwined cell must not escape from the phagosome of the other cell and must be broken down by its lysosome . 2. Both cells involved are of the same type; professional phagocytes are not involved. 3. Substances that can be used to block caspase-dependent or -independent intrinsic apoptosis do not stop the process.

Parthanatos

The trunk word denotes a death (Greek thanatos ) by the enzyme poly (ADP-ribose) polymerase 1 , or PARP1 for short. It usually helps repair DNA damage, but when it is overactivated, the cell loses too much NAD + and ATP , and the apoptosis induction factor (AIF) is released. This death program occurs in strokes, diabetes, inflammation and neurodegenerative diseases, is independent of caspases and is possibly one of the regulated necroses.

Pyroptosis

Initially described in the case of Salmonella-infected macrophages, this death program is by no means limited to macrophages and bacterial infections (also with Shigella, Listeria, Pseudomonas, etc.). Pyroptotic cells can resemble both necrotic and apoptotic cells. The enzyme caspase-1 is activated in them, and it is still unclear whether this is a special form of caspase-dependent intrinsic apoptosis. The inflammation and fever-promoting (pyrogenic) interleukins IL-1β and Il-18 are involved in its execution .

NETose

Neutrophils and eosinophilic granulocytes can be stimulated by stimuli such as bacterial molecules to release so-called neutrophilic extracellular networks (NETs for short), which mainly consist of contents of their cell nuclei such as DNA and histones and have an antimicrobial effect. Under physiological conditions, the cells do not die, despite the loss of part of their nucleus. When stimulated with certain artificial compounds, however, a special death program is triggered in some neutrophils, the NETose. It is often, but not always, associated with the release of NETs, ​​is not caspase-dependent, but is dependent on the enzymatic formation of hyperoxides and on parts of the autophagy machinery. It is partly similar to autophagic cell death and partly to regulated necrosis.

Keratinization

The cells of the outer layer of our epidermis die in a controlled manner and thus form the stratum corneum : a layer of dead keratinocytes, which largely consist of certain proteins such as keratin and fats, and make the skin stable, resistant, elastic and water-repellent. It is true that other cells also undergo a similar terminal differentiation, such as red blood cells or the cells in the lens epithelium, which lose their cell nuclei in the process. But unlike these, the keratinocytes cannot subsequently die from stress-related death. Therefore, keratinization is viewed as a separate death program.

Phases of programmed cell death

The NCCD divides regulated cell death into three phases and nine steps.

The first steps are part of the reversible phase and can be prevented or stopped by suitable cytoprotective, i.e. cell-protecting measures:

  1. Disruption of homeostasis
  2. early signaling pathways
  3. Point of no return

This is followed by the irreversible phase in which cytoprotective measures no longer bear fruit:

  1. late signal pathways
  2. immediate causes or effectors of regulated cell death
  3. primary cell death

In the third, the avoidable phase , cell death spreads to the neighborhood if it is not prevented - for example with medication:

  1. Release of hazard signals ( damage-associated molecular patterns , DAMPs)
  2. Inflammatory reactions
  3. Initiation of secondary regulated cell death (partly directly by the DAMPs, partly by the inflammation)

Failures in attempts to slow down excessive programmed cell death, for example by using caspase inhibitors, are presumably due to the fact that they begin in the irreversible phase and only stop part of the parallel dying processes. The caspases are presumably not responsible for primary cell death, but rather the loss of ATP and the disruption of the redox balance, which deactivate numerous enzymes and damage the cell's organelles and membranes.

More promising is the strengthening of survival signals, which compete with the early death program signals at the beginning of the dying process, immediately after the disturbance of homeostasis. Interventions in the late phase can still be useful if they prevent the release of DAMPs and thus the spread of death to the neighboring tissue.

Web links

Individual evidence

  1. ↑ Carl Vogt: Investigations into the history of the development of the midwife toad (Alytes obstetricans) . Jent and Gassman, Solothurn 1842 ( full text in the Google book search).
  2. ↑ JF Kerr, AH Wyllie, AR Currie: Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics . In: British Journal of Cancer . No. 26 , 1972, p. 239-257 , PMID 16313474 .
  3. ^ L. Galluzzi, I. Vitale, JM Abrams, ES Alnemri, EH Baehrecke: Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 . In: Cell Death & Differentiation . tape 19 , no. 1 , January 1, 2012, ISSN  1350-9047 , p. 107–120 , doi : 10.1038 / cdd.2011.96 , PMID 21760595 , PMC 3252826 (free full text) - ( nature.com [accessed on May 22, 2017]).
  4. ↑ Lorenzo Galluzzi, Ilio Vitale, Stuart A. Aaronson, John M. Abrams, Dieter Adam: Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 . In: Cell Death and Differentiation . tape 25 , no. 3 , March 2018, ISSN  1476-5403 , p. 486-541 , doi : 10.1038 / s41418-017-0012-4 , PMID 29362479 , PMC 5864239 (free full text).
  5. ^ L. Galluzzi, JM Bravo-San Pedro, I. Vitale, SA Aaronson, JM Abrams: Essential versus accessory aspects of cell death: recommendations of the NCCD 2015 . In: Cell Death & Differentiation . tape 22 , no. 1 , January 1, 2015, ISSN  1350-9047 , p. 58–73 , doi : 10.1038 / cdd.2014.137 , PMID 25236395 , PMC 4262782 (free full text) - ( nature.com [accessed on May 23, 2017]).