Caspase 1
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Location (UCSC) | Chr 11: 105.03 – 105.04 Mb | Chr 9: 5.3 – 5.31 Mb | |||||||
PubMed search | [3] | [4] |
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Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved
Cellular expression
Caspase-1 is evolutionarily conserved in many eukaryotes of the Kingdom Animalia. Due to its role in the inflammatory immune response, it is highly expressed in the immune organs such as the liver, kidney, spleen, and blood (neutrophils).[10][11] Following infection, the inflammatory response increases expression of Caspase-1, by a positive feedback mechanism that amplifies the response.[11]
Structure
Caspase-1 is produced as a
Regulation
Activation
Caspase-1, normally in its physiologically inactive zymogen form, autoactivates when it is assembled into the filamentous inflammasome complex by autoproteolysis into the p10 and p20 subunits.[14][15] 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 and NLRC4, 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.[16][17]
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.[15][18][19]
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.[15][18][19]
INCA, on the other hand, directly blocks inflammasome assembly by capping Caspase-1 CARD oligomers, thus blocking further polymerization into the inflammasome filaments.[18][19][20][13]
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.[19][21]
- Inhibitors
- Belnacasan (VX-765) [22]
- Pralnacasan (VX-740) [23]
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.[13]
Inflammatory response
Once matured, the cytokines initiate downstream signaling events to induce a proinflammatory response as well as to activate the expression of antiviral 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, free radicals, and other signals associated with cellular danger, even byproducts of other immune response pathways.[24]
The mature cytokines themselves do not contain the necessary sorting sequences to enter the
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.[17] 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.[27]
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. Alternative splicing of the gene results in five transcript variants encoding distinct isoforms.[28] 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.[29][30][31] Caspase-1 activity has also been implicated in lysosome acidification following phagocytosis of bacteria[32] and immune complexes.[33]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000137752 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025888 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 4310923.
- PMID 1373520.
- ^ S2CID 4317409.
- S2CID 233351704.
- PMID 25879289.
- PMID 24398679.
- ^ PMID 26777895.
- S2CID 4281700.
- ^ PMID 27043298.
- PMID 19117953.
- ^ S2CID 15886378.
- PMID 26898120.
- ^ S2CID 16281016.
- ^ PMID 11536016.
- ^ PMID 24062743.
- PMID 15383541.
- PMID 17676277.
- PMID 30254377.
- PMID 20229566.
- S2CID 3383795.
- PMID 26559977.
- PMID 26611636.
- PMID 27932073.
- ^ "Entrez Gene: CASP1 caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)".
- PMID 24356306.
- PMID 24356113.
- PMID 33720048.
- PMID 23644505.
- PMID 29866702.
External links
- The MEROPS online database for peptidases and their inhibitors: C14.001[permanent dead link]