![Caspase-1 Zymogen](https://upload.wikimedia.org/wikipedia/commons/c/c3/Caspase-1_Zymogen.jpg)
Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that
proteolytically cleaves other proteins, such as the
precursors of the inflammatory
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s
interleukin 1β
Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
and
interleukin 18
Interleukin-18 (IL-18), also known as interferon-gamma inducing factor) is a protein which in humans is encoded by the ''IL18'' gene. The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and non ...
as well as the
pyroptosis 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 va ...
inducer
Gasdermin D
Gasdermin D (GSDMD) is a protein that in humans is encoded by the ''GSDMD'' gene on chromosome 8.
It belongs to the gasdermin family which is conserved among vertebrates and comprises six members in humans, GSDMA, GSDMB, GSDMC, GSDMD, GSDME ...
, into active mature peptides.
It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an
inflammasome
Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s,
interleukin 1β
Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
(IL-1β) and
interleukin 18
Interleukin-18 (IL-18), also known as interferon-gamma inducing factor) is a protein which in humans is encoded by the ''IL18'' gene. The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and non ...
(IL-18) as well as
pyroptosis 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 va ...
, a programmed lytic
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, as in programmed cell death, or may result from factors such as d ...
pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.
Cellular expression
Caspase-1 is evolutionarily conserved in many
eukaryotes of the
Kingdom
Kingdom commonly refers to:
* A monarchy ruled by a king or queen
* Kingdom (biology), a category in biological taxonomy
Kingdom may also refer to:
Arts and media Television
* ''Kingdom'' (British TV series), a 2007 British television drama s ...
Animal
Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...
ia. Due to its role in the inflammatory immune response, it is highly expressed in the immune organs such as the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
,
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
,
spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . , and
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...
(
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s).
Following infection, the inflammatory response increases expression of Caspase-1, by a
positive feedback
Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in th ...
mechanism that amplifies the response.
Structure
Caspase-1 is produced as a
zymogen
In biochemistry, a zymogen (), also called a proenzyme (), is an inactive precursor of an enzyme. A zymogen requires a biochemical change (such as a hydrolysis reaction revealing the active site, or changing the configuration to reveal the activ ...
that can then be cleaved into 20 kDa (p20) and 10 kDa (p10) subunits that become part of the active enzyme. Active Caspase 1 contains two
heterodimers of p20 and p10. It contains a catalytic domain with an active site that spans both the p20 and p10 subunits, as well as a noncatalytic Caspase Activation and Recruitment Domain (
CARD Card or The Card may refer to:
* Various types of plastic cards:
**By type
***Magnetic stripe card
*** Chip card
*** Digital card
**By function
***Payment card
****Credit card
**** Debit card
****EC-card
****Identity card
****European Health Insur ...
) . It interacts with other
CARD Card or The Card may refer to:
* Various types of plastic cards:
**By type
***Magnetic stripe card
*** Chip card
*** Digital card
**By function
***Payment card
****Credit card
**** Debit card
****EC-card
****Identity card
****European Health Insur ...
containing proteins such as Apoptosis-Associated Speck-like Protein Containing a CARD (
ASC) and Nod-Like Receptor (
NLR) Family CARD Domain-Containing Protein 4 (
NLRC4
NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the ''NLRC4'' gene.
Structure
The NLRC4 protein is highly conserved across mammalian species. It bears homology to the ''C. elegans'' Ced4 protein. It contai ...
) through CARD-CARD interactions in the formation of inflammasomes.
Regulation
Activation
![CARD-CARD ring](https://upload.wikimedia.org/wikipedia/commons/6/6a/CARD-CARD_ring.jpg)
Caspase-1, normally in its physiologically inactive zymogen form, autoactivates when it is assembled into the filamentous
inflammasome
Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
complex by autoproteolysis into the p10 and p20 subunits.
The inflammasome complex is a ring complex composed of trimers of a signal specific sensor protein such as those of the
NLR family and the AIM-1 (Absent in Melanoma) like receptors, an adaptor protein such as ASC, and a caspase, in this case Caspase-1. In some cases, where the signaling proteins contain their own CARDs, like in
NLRP1
NLRP1 encodes NACHT, LRR, FIIND, CARD domain and PYD domains-containing protein 1 in humans. NLRP1 was the first protein shown to form an inflammasome. Material was copied from this source, which is available under Creative Commons Attribution 4. ...
and
NLRC4
NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the ''NLRC4'' gene.
Structure
The NLRC4 protein is highly conserved across mammalian species. It bears homology to the ''C. elegans'' Ced4 protein. It contai ...
, the CARD –CARD interaction is direct, meaning there is no adaptor protein in the complex. There are a variety of sensor and adaptor proteins, the various combinations of which confer the inflammasomes' responses to specific signals. This allows the cell to have varying degrees of inflammatory responses based on the severity of the danger signal received.
Inhibition
CARD only proteins (COPs) as their name implies, are proteins that only contain the non-catalytic CARDs. Owing to the importance of CARD-CARD interactions in inflammasome formation, many COPs are known inhibitors of Caspase activation. For Caspase-1, genes for specific COPs—ICEBERG, COP1 (ICE/Pseudo-ICE), and INCA (Inhibitory Card)—are all found near its locus, and are thus thought to have emerged from gene duplication events and subsequent deletions of the catalytic domains. Though they all interact with the inflammasomes using CARD–CARD interactions, they differ in the way they carry out their inhibitory functions as well as in their effectiveness at doing so.
For example, ICEBERG nucleates the formation of Caspase-1 filaments and is thus incorporated into the filaments, but lacks the ability to inhibit the activation of inflammasomes. Instead, it is thought to inhibit Caspase-1 activation by interfering with the interaction of Caspase-1 with other important CARD containing proteins.
INCA, on the other hand, directly blocks inflammasome assembly by capping Caspase-1 CARD
oligomers, thus blocking further polymerization into the inflammasome filaments.
Similarly, some POPs (Pyrin only proteins) are also known to regulate Caspase-1 activation through inhibition of inflammasome activation by binding to and blocking PYD interactions, which also play a role in the formation of the inflammasomes, though the exact mechanisms are not yet well established.
;Inhibitors
*
Belnacasan (VX-765)
*
Pralnacasan (VX-740)
Function
Proteolytic cleavage
Activated Caspase 1 proteolytically cleaves pro IL-1β and pro IL-18 into their active forms, IL-1β and IL-18. The active cytokines lead to a downstream inflammatory response. It also cleaves Gasdermin D into its active form, which leads to pyroptosis.
Inflammatory response
Once matured, the cytokines initiate downstream signaling events to induce a
proinflammatory
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
response as well as to activate the expression of
antiviral
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do no ...
genes. The speed, specificity and types of response are dependent on the signal received as well as the sensor protein that received it. Signals that can be received by the inflammasomes include
viral double stranded RNA,
urea
Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid.
Urea serves an important ...
,
free radicals, and other signals associated with cellular danger, even byproducts of other immune response pathways.
The mature cytokines themselves do not contain the necessary sorting sequences to enter the
ER-Golgi secretory pathway, and thus are not excreted from the cell by conventional methods. However, it is theorized that the release of these
proinflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include inte ...
s is not reliant on cellular rupture via
pyroptosis 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 va ...
, and is in fact, an active process. There exists evidence both for and against this hypothesis. The fact that for many cell types, the cytokines are secreted despite them showing absolutely no signs of pyroptosis, supports this hypothesis.
However, some experiments show that Gasdermin D nonfunctional mutants still had normal cleavage of the cytokines but lacked the ability to secrete them, indicating pyroptosis may in fact be necessary for secretion in some way.
Pyroptosis response
Following the inflammatory response, an activated Caspase-1 can induce pyroptosis, a lytic form of cell death, depending on the signal received as well as the specific inflammasome sensor domain protein that received it. Though pyroptosis may or may not be required for the full inflammatory response, the inflammatory response is fully required before pyroptosis can occur.
In order to induce pyroptosis, Caspase-1 cleaves Gasdermin D into fragments that form pores in the plasma membrane. As a result of osmotic pressure, these pores promote the influx of fluid, resulting in cell lysis and death.
Other roles
Caspase-1 has also been shown to induce
necrosis and may also function in various developmental stages. Studies of a similar protein in mice suggest a role in the pathogenesis of
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
.
Alternative splicing of the gene results in five transcript variants encoding distinct isoforms. Recent studies implicated caspase-1 in promoting CD4 T-cell death and inflammation by HIV, two signature events that fuel HIV disease progression to AIDS.
Caspase-1 activity has also been implicated in lysosome acidification following phagocytosis of bacteria and immune complexes.
See also
*
The Proteolysis Map
The Proteolysis MAP (PMAP) is an integrated web resource focused on proteases.
Rationale
PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.
History and funding
PMAP was originally created ...
*
Caspase
*
Pyroptosis 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 va ...
*
Inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
*
Inflammasome
Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
References
External links
* The
MEROPS
MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibit ...
online database for peptidases and their inhibitors
C14.001
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EC 3.4.22
Caspases