Caspase-1
Also known as: CASP1, IL1BC, IL1BCE
Function
Thiol protease involved in a variety of inflammatory processes by proteolytically cleaving other proteins, such as the precursors of the inflammatory cytokines interleukin-1 beta (IL1B) and interleukin 18 (IL18) as well as the pyroptosis inducer Gasdermin-D (GSDMD), into active mature peptides. Plays a key role in cell immunity as an inflammatory response initiator: once activated through formation of an inflammasome complex, it initiates a pro-inflammatory response through the cleavage of the two inflammatory cytokines IL1B and IL18, releasing the mature cytokines which are involved in a variety of inflammatory processes. Cleaves a tetrapeptide after an Asp residue at position P1. Also initiates pyroptosis, a programmed lytic cell death pathway, through cleavage of GSDMD. In contrast to cleavage of interleukin IL1B, recognition and cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP1 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part. Cleaves and activates CASP7 in response to bacterial infection, promoting plasma membrane repair. Upon inflammasome activation, during DNA virus infection but not RNA virus challenge, controls antiviral immunity through the cleavage of CGAS, rendering it inactive. In apoptotic cells, cleaves SPHK2 which is released from cells and remains enzymatically active extracellularly.
Classification
- Family (Pfam)
- PF00619 CARD, PF00656 Peptidase_C14
- InterPro
- CARD, Caspase-like_dom_sf, Caspase_cys_AS, Caspase_his_AS, DEATH-like_dom_sf, Pept_C14, Pept_C14_caspase, Pept_C14_p10, Pept_C14_p20, Pept_C14A
- Functional cluster
- Immunoglobulin & Immune-Response Proteins
Experimental structures · PDB · 42
- 1BMQ X-ray 2.50A
- 1IBC X-ray 2.73A
- 1ICE X-ray 2.60A
- 1RWK X-ray 2.30A
- 1RWM X-ray 2.70A
- 1RWN X-ray 2.00A
- 1RWO X-ray 2.10A
- 1RWP X-ray 2.20A
- 1RWV X-ray 2.10A
- 1RWW X-ray 2.80A
- 1RWX X-ray 1.85A
- 1SC1 X-ray 2.60A
- … and 30 more
A predicted model is available from AlphaFold.
Gene Ontology · 43
- GO:0097169 AIM2 inflammasome complex
- GO:0005737 cytoplasm
- GO:0005829 cytosol
- GO:0072557 IPAF inflammasome complex
- GO:0005874 microtubule
- GO:0072558 NLRP1 inflammasome complex
- GO:0072559 NLRP3 inflammasome complex
- GO:0005730 nucleolus
- GO:0005886 plasma membrane
- GO:0097179 protease inhibitor complex
- GO:0032991 protein-containing complex
- GO:0050700 CARD domain binding
- GO:0008656 cysteine-type endopeptidase activator activity involved in apoptotic process
- GO:0004197 cysteine-type endopeptidase activity
- GO:0019955 cytokine binding
- GO:0004175 endopeptidase activity
- GO:0042802 identical protein binding
- GO:0019900 kinase binding
- GO:0140970 AIM2 inflammasome complex assembly
- GO:0006915 apoptotic process
- GO:0071222 cellular response to lipopolysaccharide
- GO:0071260 cellular response to mechanical stimulus
- GO:0071346 cellular response to type II interferon
- GO:0140447 cytokine precursor processing
- GO:0042742 defense response to bacterium
- GO:0051607 defense response to virus
- GO:0046456 icosanoid biosynthetic process
- GO:0007231 osmosensory signaling pathway
- GO:0002221 pattern recognition receptor signaling pathway
- GO:0043065 positive regulation of apoptotic process
- GO:0043123 positive regulation of canonical NF-kappaB signal transduction
- GO:0050729 positive regulation of inflammatory response
- GO:0032731 positive regulation of interleukin-1 beta production
- GO:0032741 positive regulation of interleukin-18 production
- GO:1903265 positive regulation of tumor necrosis factor-mediated signaling pathway
- GO:0016540 protein autoprocessing
- GO:0051604 protein maturation
- GO:0016485 protein processing
- GO:0006508 proteolysis
- GO:0070269 pyroptotic inflammatory response
- GO:0050727 regulation of inflammatory response
- GO:0007165 signal transduction
- GO:0140448 signaling receptor ligand precursor processing
Drugs targeting this protein · 3
- EMRICASAN inhibitor
- NIVOCASAN inhibitor
- BELNACASAN inhibitor
Neighborhood · nearest proteins
Related proteins · sequence + function similarity
- Caspase-1 0.97
- Caspase-1 0.97
- Caspase-1 0.96
- Caspase-1 0.96
- Caspase-1 0.94
- Caspase-1 0.94
- Caspase-13 0.93
- Caspase-4 0.93
- Caspase-4 0.89
- Caspase-12 0.88
- Caspase-12 0.87
- Caspase-12 0.87
Co-cited proteins · studied together in the literature
- Putative caspase recruitment domain-containing protein 17P 1 shared papers
- Serine proteinase inhibitor 2 1 shared papers
- Caspase recruitment domain-containing protein 18 1 shared papers
- Interleukin-18 3 shared papers
- Sphingosine kinase 2 1 shared papers
- Interleukin-1 beta 2 shared papers
- Pyrin 1 shared papers
- Gasdermin-D 3 shared papers
- Caspase recruitment domain-containing protein 8 3 shared papers
- Caspase-4 6 shared papers
- Caspase-1 4 shared papers
- Ubiquitin carboxyl-terminal hydrolase 8 1 shared papers
Literature · 31 cited papers
- Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome. Nature · 2023
- Mechanism of filament formation in UPA-promoted CARD8 and NLRP1 inflammasomes. Nat. Commun. · 2021
- Caspase-1 engages full-length Gasdermin D through two distinct interfaces that mediate caspase recruitment and substrate cleavage. Immunity · 2020
- Structural mechanism for GSDMD targeting by autoprocessed caspases in pyroptosis. Cell · 2020
- Caspase-1 interdomain linker cleavage is required for pyroptosis. Life. Sci Alliance · 2020
- SERPINB1-mediated checkpoint of inflammatory caspase activation. Nat. Immunol. · 2019
- Zika virus elicits inflammation to evade antiviral response by cleaving cGAS via NS1-caspase-1 axis. EMBO J. · 2018
- Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to regulate responses to DNA virus infection. Immunity · 2017
- Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature · 2015
- Inflammasome-activated caspase 7 cleaves PARP1 to enhance the expression of a subset of NF-kappaB target genes. Mol. Cell · 2012
- Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
- Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from apoptotic cells. Blood · 2010
- … and 19 more in the literature graph