non-canonical inflammasome complex
Definition
Target type: cellularcomponent
An inflammasome complex containing CASP4, known as caspase-11 (Casp11) in mouse, which assembles upon cytosolic lipopolysaccharide-binding and directly activates Gasdermin-D (GSDMD). [PMID:33187725]
The non-canonical inflammasome complex is a protein complex that triggers the production of pro-inflammatory cytokines, such as IL-1β, in response to microbial infections. It differs from the canonical inflammasome in its mode of activation and the proteins involved. While the canonical inflammasome relies on the adaptor protein ASC and the effector caspase-1, the non-canonical inflammasome utilizes caspase-4/5/11 (in humans) or caspase-11 (in mice) as the effector caspase and does not require ASC.
The cellular component of the non-canonical inflammasome complex is characterized by its association with the endoplasmic reticulum (ER) membrane. This association is crucial for its activation. Upon sensing bacterial LPS (lipopolysaccharide) or other danger signals, caspase-4/5/11 undergoes activation in the ER lumen. This activation process involves the interaction of caspase-4/5/11 with specific adaptor proteins like the NLRP3 inflammasome, which can also interact with the ER membrane. The activated caspase-4/5/11 then cleaves Gasdermin D (GSDMD), a protein residing in the ER membrane. Cleaved GSDMD translocates to the plasma membrane, where it forms pores, leading to the release of IL-1β and other pro-inflammatory mediators.
The exact composition of the non-canonical inflammasome complex is still under investigation, but it involves various proteins besides caspase-4/5/11 and GSDMD. These include, but are not limited to, adaptor proteins, such as NLRP3 and NLRC4, which contribute to signal transduction, as well as chaperone proteins, which aid in protein folding and trafficking. The cellular component of this complex is dynamic, undergoing constant changes in its protein composition and cellular localization during its activation cycle.
Overall, the non-canonical inflammasome complex exists as a dynamic assembly of proteins associated with the ER membrane. Its activation, triggered by the sensing of microbial or danger signals, involves a complex interplay of proteins leading to the release of pro-inflammatory cytokines and cellular pyroptosis. This complex represents an important defense mechanism against microbial infections, but it can also contribute to the pathogenesis of inflammatory diseases.'
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Proteins (1)
| Protein | Definition | Taxonomy |
|---|---|---|
| Caspase-4 | A caspase-4 that is encoded in the genome of human. [PRO:WCB, UniProtKB:P49662] | Homo sapiens (human) |
Compounds (13)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| 4-biphenylylacetic acid | biphenyl-4-ylacetic acid : A monocarboxylic acid in which one of the alpha-hydrogens is substituted by a biphenyl-4-yl group. An active metabolite of fenbufen, it is used as a topical medicine to treat muscle inflammation and arthritis. | biphenyls; monocarboxylic acid | non-steroidal anti-inflammatory drug |
| fenbufen | fenbufen: structure; RN given refers to parent cpd | 4-oxo monocarboxylic acid; biphenyls | non-steroidal anti-inflammatory drug |
| ibuprofen | Midol: combination of cinnamedrine, phenacetin, aspirin & caffeine | monocarboxylic acid | antipyretic; cyclooxygenase 1 inhibitor; cyclooxygenase 2 inhibitor; drug allergen; environmental contaminant; geroprotector; non-narcotic analgesic; non-steroidal anti-inflammatory drug; radical scavenger; xenobiotic |
| indoprofen | indoprofen : A monocarboxylic acid that is propionic acid in which one of the hydrogens at position 2 is substituted by a 4-(1-oxo-1,3-dihydroisoindol-2-yl)phenyl group. Initially used as an anti-inflammatory and analgesic, it was withdrawn from the market due to causing severe gastrointestinal bleeding. It has been subsequently found to increase production of the survival motor neuron protein. Indoprofen: A drug that has analgesic and anti-inflammatory properties. Following reports of adverse reactions including reports of carcinogenicity in animal studies it was withdrawn from the market worldwide. (From Martindale, The Extra Pharmacopoeia, 30th ed, p21) | gamma-lactam; isoindoles; monocarboxylic acid | EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor; non-narcotic analgesic; non-steroidal anti-inflammatory drug |
| ketoprofen | ketoprofen : An oxo monocarboxylic acid that consists of propionic acid substituted by a 3-benzoylphenyl group at position 2. Ketoprofen: An IBUPROFEN-type anti-inflammatory analgesic and antipyretic. It is used in the treatment of rheumatoid arthritis and osteoarthritis. | benzophenones; oxo monocarboxylic acid | antipyretic; drug allergen; EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor; environmental contaminant; non-steroidal anti-inflammatory drug; xenobiotic |
| ketorolac | 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid : A member of the class of pyrrolizines that is 2,3-dihydro-1H-pyrrolizine which is substituted at positions 1 and 5 by carboxy and benzoyl groups, respectively. ketorolac : A racemate comprising equimolar amounts of (R)-(+)- and (S)-(-)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid. While only the (S)-(-) enantiomer is a COX1 and COX2 inhibitor, the (R)-(+) enantiomer exhibits potent analgesic activity. A non-steroidal anti-inflammatory drug, ketorolac is mainly used (generally as the tromethamine salt) for its potent analgesic properties in the short-term management of post-operative pain, and in eye drops to relieve the ocular itching associated with seasonal allergic conjunctivitis. It was withdrawn from the market in many countries in 1993 following association with haemorrhage and renal failure. Ketorolac: A pyrrolizine carboxylic acid derivative structurally related to INDOMETHACIN. It is an NSAID and is used principally for its analgesic activity. (From Martindale The Extra Pharmacopoeia, 31st ed) | amino acid; aromatic ketone; monocarboxylic acid; pyrrolizines; racemate | analgesic; cyclooxygenase 1 inhibitor; cyclooxygenase 2 inhibitor; non-steroidal anti-inflammatory drug |
| tiaprofenic acid | tiaprofenic acid : An aromatic ketone that is thiophene substituted at C-2 by benzoyl and at C-4 by a 1-carboxyethyl group. tiaprofenic acid: RN given refers to parent cpd; structure | aromatic ketone; monocarboxylic acid; thiophenes | drug allergen; non-steroidal anti-inflammatory drug |
| n-methylisatin | N-methylisatin: structure given in first source | ||
| naproxen | naproxen : A methoxynaphthalene that is 2-methoxynaphthalene substituted by a carboxy ethyl group at position 6. Naproxen is a non-steroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as osteoarthritis, kidney stones, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, menstrual cramps, tendinitis, bursitis, and for the treatment of primary dysmenorrhea. It works by inhibiting both the COX-1 and COX-2 enzymes. Naproxen: An anti-inflammatory agent with analgesic and antipyretic properties. Both the acid and its sodium salt are used in the treatment of rheumatoid arthritis and other rheumatic or musculoskeletal disorders, dysmenorrhea, and acute gout. | methoxynaphthalene; monocarboxylic acid | antipyretic; cyclooxygenase 1 inhibitor; cyclooxygenase 2 inhibitor; drug allergen; environmental contaminant; gout suppressant; non-narcotic analgesic; non-steroidal anti-inflammatory drug; xenobiotic |
| 5-Nitroisatin | indoles | anticoronaviral agent | |
| 6-(3,5-difluoroanilino)-9-ethyl-2-purinecarbonitrile | 6-aminopurines | ||
| grassystatin a | grassystatin A: isolated from a cyanobacterium, identified as Lyngbya cf.; structure in first source | ||
| MK-8353 | MK-8353 : A member of the class of indazoles that is 1H-indazole substituted by a 6-(propan-2-yloxy)pyridin-3-yl group at position 3 and by a {[(3S)-3-(methylsulfanyl)-1-(2-{4-[4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]-3,6-dihydropyridin-1(2H)-yl}-2-oxoethyl)pyrrolidin-3-yl]carbonyl}amino group at position 5. It is a potent and selective inhibitor of ERK1 and ERK2 in vitro (IC50 values of 23.0 nM and 8.8 nM, respectively). The drug is being developed by Merck Sharp & Dohme and is currently in clinical development for the treatment of advanced/metastatic solid tumors. MK-8353: ERK inhibitor used in oncology | aromatic ether; dihydropyridine; indazoles; methyl sulfide; N-alkylpyrrolidine; pyridines; pyrrolidinecarboxamide; secondary carboxamide; tertiary carboxamide; triazoles | antineoplastic agent; apoptosis inducer; EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor |