出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2017/01/05 05:28:42」(JST)
Caspase domain | |||||||||
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Structure of interleukin-1 beta-converting enzyme.[1]
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Identifiers | |||||||||
Symbol | Peptidase_C14 | ||||||||
Pfam | PF00656 | ||||||||
Pfam clan | CL0093 | ||||||||
InterPro | IPR002398 | ||||||||
PROSITE | PS50208 | ||||||||
MEROPS | C14 | ||||||||
SCOP | 1ice | ||||||||
SUPERFAMILY | 1ice | ||||||||
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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 at the C-terminal of an aspartic acid amino acid. As of 2009, there are 11-12 confirmed Caspases in humans (since caspase-12 is a pseudogene in some individuals; Nature Medicine 11, 725 - 730 (2005)) 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 ensure that the cellular components are degraded in a controlled manner, carrying out cell death with minimal effect to surrounding tissues.[2]
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[3]
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 restrains of cell growth, combined with mutations in apoptopic proteins such as Caspases that would respond by inducing cell death in abnormal growing cells.[4] On the contrary, 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 Alzheimers disease.[4] Caspases involved with processing inflammatory signals are also implicated in disease. Insufficient activation of these caspases can increase the organisms susceptibility to infection as an appropriate immune response may not be activated.[4] The integral role caspases play in cell death and disease has led to research for 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.[5]
Most caspases play a role in programmed cell death. These are summarised in the table below. The enzymes are sub classified into three types: Initiator, Executioner and Inflammatory.[6]
Programmed Cell Death | Type of Caspase | Enzyme | Organism |
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Apoptosis | Initiator | Caspase 2 | human and mouse |
Caspase 8 | human and mouse | ||
Caspase 9 | human and mouse | ||
Caspase 10 | human only (Science. 2006 Jun 30;312(5782):1874. Caspase-10 in mouse or not? Jänicke RU, Sohn D, Totzke G, Schulze-Osthoff K.) | ||
Executioner | Caspase 3 | human and mouse | |
Caspase 6 | human and mouse | ||
Caspase 7 | human and mouse | ||
Pyroptosis | Inflammatory | Caspase 1 | human and mouse |
Caspase 4 | human | ||
Caspase 5 | human | ||
Caspase 11 | mouse | ||
Caspase 12 | mouse and some humans | ||
Other roles | Other | Caspase 14 | human and mouse |
Note that in addition to apoptosis, Caspase-8 is also required for the inhibition of another form of programmed cell death called Necroptosis. Caspase-14 plays a role in epithelial cell keratinocyte differentiation and can form an epidermal barrier that protects against dehydration and UVB radiation.[7]
Caspases are synthesised as inactive zymogens (pro-caspases) that are only activated following an appropriate stimulus. This post-translational level of control allows rapid and tight regulation of the enzyme.
Activation involves dimerization and often oligomerisation of pro-caspases, followed by cleavage into a small subunit and large subunit. The large and small subunit associate with each other to form an active heterodimer caspase. The active enzyme often exists as a heterotetramer in the biological environment, where a pro-caspase dimer is cleaved together to form a heterotetramer.[8]
Dimerisation is facilitated by a particular domain called the pro-domain. This domain is larger in Initiator and Inflammatory Caspases, consisting of Caspase Recruitment Domains (CARD) and Death Effector Domains (DED), used to mediate protein-protein interactions between caspases. Adaptor proteins are used by some caspases, to assist this interaction.
Multiprotein complexes often form during pro-caspase activation.[8] Some activating multiprotein complexes includes:
Once appropriately dimerised, the Caspases cleaves at inter domain linker regions, forming a large and small subunit. This cleavage allows the active-site loops to take up a conformation favourable for enzymatic activity.[9]
Cleavage of Initiator and Executioner caspases occur by different methods outlined in the table below.
Initiator Caspase
Caspase-8 |
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Executioner
Caspase Caspase-3 |
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Apoptosis is a form of programmed cell death where the cell undergoes morphological changes, to minimize its effect on surrounding cells to avoid inducing an immune response. The cell shrinks and condenses - the cytoskeleton will collapse, the nuclear envelope disassembles and the DNA fragments up. This results in the cell forming self-enclosed bodies called 'blebs', to avoid release of cellular components into the extracellular medium. Additionally, the cell membrane phospholipid content is altered, which makes the dying cell more susceptible to phagocytic attack and removal.[11]
Apoptopic caspases are subcategorised as:
Once initiator caspases are activated, they produce a chain reaction, activating several other executioner caspases. Executioner caspases degrade over 600 cellular components[12] in order to induce the morphological changes for apoptosis.
Examples of caspase cascade during apoptosis:
Pyroptosis is a form of programmed cell death that inherently induces an immune response. It is morphologically distinct from other types of cell death – cells swell up, rupture and release pro-inflammatory cellular contents. This is done in response to a range of stimuli including microbial infections as well as heart attacks (myocardial infarctions).[14] Caspase-1, Caspase-4 and Caspase-5 in humans whereas Caspase-1 and Caspase-11 in mice play important roles in inducing cell death by Pyroptosis. This could lead to limiting the life and proliferation time of intracellular and extracellular pathogens.
Caspase-1 activation is mediated by a repertoire of proteins, allowing detection of a range of pathogenic ligands. Some mediators of Caspase-1activation are: NOD-like Leucine Rich Repeats (NLRs), AIM2-Like Receptors (ALRs), Pyrin and IFI16.[15]
These proteins allow caspase-1 activation by forming a multiprotein activating complex called Inflammasomes. For example, a NOD Like Leucine Rich Repeat NLRP3 will sense an efflux of potassium ions from the cell. This cellular ion imbalance leads to oligomerisation of NLRP3 molecules to form a multiprotein complex called the NLRP3 Inflammasome. The pro-caspase-1 is brought into close proximity with other pro-caspase molecule in order to dimerise and undergo auto-proteolytic cleavage.[15]
Some pathogenic signals that lead to Pyroptosis by Caspase-1 are listed below:
Pyroptosis by Caspase -4 and Caspase-5 in humans and Caspase-11 in mice
These caspases have the ability to induce direct pyroptosis when LPS molecules (found in the cell wall of gram negative bacteria) are found in the cytoplasm of the host cell. For example, Caspase 4 acts as a receptor and is proteolytically activated, without the need of an inflammasome complex or Caspase-1 activation.[15]
A crucial downstream substrate for pyroptopic caspases is Gasdermin D (GSDMD)[16]
Inflammation is a protective attempt by an organism to restore a homeostatic state, following disruption from harmful stimulus, such as tissue damage or bacterial infection.[12]
Caspase-1, Caspase-4, Caspase-5 and Caspase-11 are considered 'Inflammatory Caspases'.[6]
H. Robert Horvitz initially established the importance of caspases in apoptosis and found that the ced-3 gene is required for the cell death that took place during the development of the nematode C. elegans. Horvitz and his colleague Junying Yuan found in 1993 that the protein encoded by the ced-3 gene is cysteine protease with similar properties to the mammalian interleukin-1-beta converting enzyme (ICE) (now known as caspase 1). At the time, ICE was the only known caspase.[17] Other mammalian caspases were subsequently identified, in addition to caspases in organisms such as fruit fly Drosophila melanogaster.
Researchers decided upon the nomenclature of the caspase in 1996. In many instances, a particular caspase had been identified simultaneously by more than one laboratory, who would each give the protein a different name. For example, caspase 3 was variously known as CPP32, apopain and Yama. Caspases, therefore, were numbered in the order in which they were identified.[18] ICE was, therefore, renamed as caspase 1. ICE was the first mammalian caspase to be characterised because of its similarity to the nematode death gene ced-3, but it appears that the principal role of this enzyme is to mediate inflammation rather than cell death.
Proteases: cysteine proteases (EC 3.4.22)
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Caspase |
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Fruit-derived |
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Calpain |
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Cathepsin |
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Other |
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Apoptosis signaling pathway
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Fas path |
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TNF path |
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Other |
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リンク元 | 「カスパーゼ」「カスペース」 |
拡張検索 | 「caspase 1」「caspase inhibitor」「caspase recruitment domain」 |
Family | Caspase | Other Name | Recognition | Target (Truncation site) |
caspase-1 | caspase-1 | ICE | WEHD | pro IL-1β (FEAD/G, YVHD/A), procaspase-3, procaspase-4 |
caspase-4 | ICErel-II, TX, ICH-2 | |||
caspase-5 | ICErel-III, TY | |||
caspase-2 | caspase-2 | ICH-1 | DEHD | PARP (DEVD/G) |
caspase-9 | ICE-LAP6, Mch6 | LEHD | PARP, procaspase-3 | |
caspase-3 | caspase-3 | CPP32, Yama | DEVD | PARP, SREBP (DEPD/S), U1snRNP (DGPD/G), lamin B, D4-GDI (DELD/S), DNA-PK (DEVD/N), DFF (DETD/S, DAVD/T), actin (ELPD/G) ?, PKCδ (DMQD/N) ?]] |
caspase-7 | Mch3, ICE-LAP3, CMH-1 | DEVD | PARP, procaspase-6 | |
caspase-6 | Mch2 | VEHD | lamin A (VEID/N)]] | |
caspase-8 | FLICE, MACH, Mch5 | LETD | procaspase-3, Bid | |
caspase-10 | Mch4 | LEXD | ||
caspase-11 | Ich3 |