The regulation and stimulation of apoptosis. Apoptosis is driven by internal (intrinsic pathway) and external (extrinsic pathway) signals, and can also be induced by immune cells. Cells undergoing apoptosis tend to shrink, condense, and detach from surfaces including other cells. They develop blebs, fragment their nuclei and DNA (karyorrhexis), and recruit macrophages by displaying phosphatidylserine on their surface.
The extrinsic pathway funnels signals to the cell from its environmental context, while the intrinsic pathway tells the cell to die when it is under stress. Internal death stimuli include DNA damage, unfolded proteins, reactive oxygen species, oncogene activation, infection, toxic insult, and heat shock. Both pathways funnel through to the caspase proteins, which lie at the core of apoptosis by proteolytically cleaving their many targets to either deactivate them or give them specific apoptotic functions.
The cysteine-dependent, aspartate-directed proteases (caspases) exist as zymogens when inactive. When conditions are favourable, (that is, during a death response,) procaspases dimerise and reciprocally activate by mutual proteolytic cleavage. The resulting caspases are then fully competent to cleave its downstream targets.
There are two types of caspase: initiators and executioners. Initiator caspases are the first ones to respond to the death signal, and their activity is to activate other caspases - both initiators and executioners. They contain CARDs (caspase recruitment domains) and DEDs (death execution domains). Executioner caspases have many downstream targets which are responsible for the morphological changes that apoptotic cells undergo. For example, executioner caspases can target cell-cell and cell-extracellular matrix contacts, leading to detachment; they can target ROCK, activating its function to increase actinomyosin force and leading to blebbing; they can cleave nuclear lamin B, leading to nuclear envelope breakdown; and they can destroy the inhibitor of caspase-activated DNase (iCAD), allowing the caspase-activated DNase (CAD) to perform karyorrhexis.
Two pathways in extrinsic activation of apoptosis are through the Fas receptor and the TNFα receptor. Signalling through a Fas ligand-bound Fas receptor leads to recruitment of FADD on the cytosolic face. FADD docks onto the Fas receptor through homotypic interactions between death domains (DDs). FADD also contains a DED, which recruits and concentrates procaspase 8, thereby leading to a caspase cascade. The last step is inhibited by FLIP, which competes with procaspase 8 for procaspase 8 binding. It blocks the formation of procaspase dimers, and so blocks the caspase cascade.
Signalling through a TNFα-bound TNFα receptor leads to recruitment of TRADD and assembly of complex I on the cytosolic face - also through a series of DD homotypic binding interactions. This can go one of two ways: it can be internalised, leading to release of complex I and processing into complex II. Complex II then uses its DDs to recruit FADD, where signals intersect with the Fas pathway. Alternatively, the receptor does not internalise, and complex I leads to signalling through NF-κB, which signals for survival, not apoptosis. cIAP disfavours complex II formation and promotes complex I retention.
The intrinsic pathway involves leakage of cytochrome c via mitochrondial outer membrane permeabilisation (MOMP), formation of the apoptosome, and concentration of procaspase 9. In response to intrinsic death stimuli, homodimers of Bax and of Bak form pores in the mitochrondrial outer membrane. Cytochrome c is then allowed to leak out of the mitochondria and bind Apaf1. In the absence of cytochrome c, Apaf1 autoinhibits by interaction between its WD40 domains. In the presence of cytochrome c, Apaf1 is allowed to oligomerise, forming the apoptosome. This interaction reveals the CARD on Apaf1, and recruits and concentrates procaspase 9, leading to a caspase cascade.
There is regulation at each of these steps. Bcl-2 is an antiapoptotic protein, which disfavours homodimerisation of Bax and of Bak, thereby preventing the formation of pores. It does this by favouring the conformation of Bax and of Bak where their BH3 domain is hidden - it is through the BH3 domain that Bax anad Bak homodimerise. XIAP is another antiapoptotic protein which binds and sequesters caspases through its BIR (bacculovirus inhibitor of apoptosis (IAP) repeat) domain. Through its RING domain, it can recruit an E3 ubiqitin ligase, and mark its binding partners for proteasomal destruction. Finally, proapoptotic Smac (second mitochondria-derived activator of caspases) and DIABLO (direct IAP-binding protein with low pI) bind XIAP on its BIR domains, thereby inactivating it.
Both cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells can induce cell death, by apoptosis or otherwise. T cells recognise cells decorated with major histocompatibility complexes (MHCs) which display foreign antigens. T cells provide the Fas ligand to these cells, ensuing death. If the cell does not have a Fas receptor, the T cell can invoke death by perforin and granzymes - perforin punches holes in the cell membrane while granzymes induce a caspase cascade, or can alternatively kill the cell independently of apoptosis.
Natural killer cells recognise MHC class I proteins on the surfaces of cells. They also recognise activating ligands on the cell surface which act to promote perforin/granzyme-induced death. The activatory signal is suppressed if the cell bears an MHC class I protein which is recognised as 'self' - absence of this elicits death by perforin and granzymes.
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