Protein: Caspase-4 (P70343)
Organism: Mus musculus (Mouse)
Function: Inflammatory caspase that acts as the effector of the non- canonical inflammasome by mediating lipopolysaccharide (LPS)-induced pyroptosis. Also indirectly activates the NLRP3 and NLRP6 inflammasomes. Acts as a thiol protease that cleaves a tetrapeptide after an Asp residue at position P1: catalyzes cleavage of CGAS and GSDMD. In contrast to its human ortholog, does not cleave IL18. Effector of the non-canonical inflammasome independently of NLRP3 inflammasome and CASP1: the non-canonical inflammasome promotes pyroptosis through GSDMD cleavage without involving secretion of cytokine IL1B and IL18. In the non-canonical inflammasome, CASP4/CASP11 is activated by direct binding to the lipid A moiety of LPS without the need of an upstream sensor. LPS-binding promotes CASP4/CASP11 activation and CASP4/CASP11-mediated cleavage of GSDMD, followed by pyroptosis of infected cells and their extrusion into the gut lumen. Also indirectly promotes secretion of mature cytokines (IL1A, IL18 and HMGB1) downstream of GSDMD-mediated pyroptosis via activation of the NLRP3 and NLRP6 inflammasomes (By similarity). Involved in NLRP3- dependent CASP1 activation and IL1B and IL18 secretion in response to non-canonical activators, such as UVB radiation or cholera enterotoxin. Involved in NLRP6 inflammasome-dependent activation in response to lipoteichoic acid (LTA), a cell-wall component of Gram- positive bacteria, which leads to CASP1 activation and IL1B and IL18 secretion. Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (By similarity). The non-canonical inflammasome is required for innate immunity to cytosolic, but not vacuolar, bacteria. Plays a crucial role in the restriction of S.typhimurium replication in colonic epithelial cells during infection. Activation of the non-canonical inflammasome in brain endothelial cells can lead to excessive pyroptosis, leading to blood-brain barrier breakdown. Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation. May also act as an activator of adaptive immunity in dendritic cells, following activation by oxidized phospholipid 1-palmitoyl-2-arachidonoyl- sn-glycero-3- phosphorylcholine, an oxidized phospholipid (oxPAPC). Cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP4/CASP11 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part. In contrast, it does not directly process IL1B. During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation
Subcellular location: Cytoplasm, cytosol. Cytoplasm. Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side. Mitochondrion. Inflammasome. Secreted. Note=Predominantly localizes to the endoplasmic reticulum (ER). Association with the ER membrane requires TMEM214. Released in the extracellular milieu by keratinocytes following UVB irradiation
Sequence: MAENKHPDKPLKVLEQLGKEVLTEYLEKLVQSNVLKLKEEDKQKFNNAERSDKRWVFVDAMKKKHSKVGEMLLQTFFSVDPGSHHGEANLEMEEPEESLNTLKLCSPEEFTRLCREKTQEIYPIKEANGRTRKALIICNTEFKHLSLRYGANFDIIGMKGLLEDLGYDVVVKEELTAEGMESEMKDFAALSEHQTSDSTFLVLMSHGTLHGICGTMHSEKTPDVLQYDTIYQIFNNCHCPGLRDKPKVIIVQACRGGNSGEMWIRESSKPQLCRGVDLPRNMEADAVKLSHVEKDFIAFYSTTPHHLSYRDKTGGSYFITRLISCFRKHACSCHLFDIFLKVQQSFEKASIHSQMPTIDRATLTRYFYLFPGN
InterPro domains: - IPR002398: Peptidase C14 family (family) [1-373]
- IPR033139: Peptidase family C14A, cysteine active site (active_site) [245-256]
- IPR001309: Peptidase C14, p20 domain (domain) [130-258]
- IPR029030: Caspase-like domain superfamily (homologous_superfamily) [109-372]
- IPR015917: Peptidase C14A, caspase catalytic domain (domain) [121-371]
- IPR011600: Peptidase C14, caspase domain (domain) [131-368]
- IPR001315: CARD domain (domain) [1-92]
- IPR011029: Death-like domain superfamily (homologous_superfamily) [4-85]
- IPR016129: Peptidase family C14A, His active site (active_site) [193-207]
- IPR002138: Peptidase C14, caspase non-catalytic subunit p10 (domain) [286-371]
Interaction partners: - Gasdermin-D
- NACHT, LRR and PYD domains-containing protein 1a
- Caspase-1
- Apoptosis-associated speck-like protein containing a CARD
- NACHT, LRR and PYD domains-containing protein 3
- NLR family CARD domain-containing protein 4
- Interferon-inducible protein AIM2
- NACHT, LRR and PYD domains-containing protein 6
- Baculoviral IAP repeat-containing protein 1e
- Baculoviral IAP repeat-containing protein 1b
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0140096 (catalytic activity, acting on a protein), GO:0016787 (hydrolase activity), GO:0005515 (protein binding), GO:0008233 (peptidase activity), GO:0008234 (cysteine-type peptidase activity), GO:0004175 (endopeptidase activity), GO:0004197 (cysteine-type endopeptidase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0008152 (metabolic process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0044419 (biological process involved in interspecies interaction between organisms), GO:0022414 (reproductive process), GO:0000003 (reproduction), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0009605 (response to external stimulus), GO:0048869 (cellular developmental process), GO:0048856 (anatomical structure development), GO:0023056 (positive regulation of signaling), GO:0019222 (regulation of metabolic process), GO:0048584 (positive regulation of response to stimulus), GO:0051240 (positive regulation of multicellular organismal process), GO:0002684 (positive regulation of immune system process), GO:0006807 (nitrogen compound metabolic process), GO:0002682 (regulation of immune system process), GO:0051239 (regulation of multicellular organismal process), GO:0071704 (organic substance metabolic process), GO:0003006 (developmental process involved in reproduction), GO:0048522 (positive regulation of cellular process), GO:0009607 (response to biotic stimulus), GO:0008219 (cell death), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0009893 (positive regulation of metabolic process), GO:0023051 (regulation of signaling), GO:0006950 (response to stress), GO:0030029 (actin filament-based process), GO:0051707 (response to other organism), GO:0044238 (primary metabolic process), GO:0009967 (positive regulation of signal transduction), GO:0060759 (regulation of response to cytokine stimulus), GO:0032103 (positive regulation of response to external stimulus), GO:0012501 (programmed cell death), GO:1901564 (organonitrogen compound metabolic process), GO:0035234 (ectopic germ cell programmed cell death), GO:0043207 (response to external biotic stimulus), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0048468 (cell development), GO:0030154 (cell differentiation), GO:0080134 (regulation of response to stress), GO:0019538 (protein metabolic process), GO:0009966 (regulation of signal transduction), GO:0006952 (defense response), GO:0060255 (regulation of macromolecule metabolic process), GO:0032101 (regulation of response to external stimulus), GO:0002700 (regulation of production of molecular mediator of immune response), GO:0060760 (positive regulation of response to cytokine stimulus), GO:0001817 (regulation of cytokine production), GO:0030036 (actin cytoskeleton organization), GO:0043170 (macromolecule metabolic process), GO:0098542 (defense response to other organism), GO:0010646 (regulation of cell communication), GO:0002702 (positive regulation of production of molecular mediator of immune response), GO:0002697 (regulation of immune effector process), GO:0009617 (response to bacterium), GO:0010623 (programmed cell death involved in cell development), GO:0010647 (positive regulation of cell communication), GO:0001819 (positive regulation of cytokine production), GO:0031349 (positive regulation of defense response), GO:0002699 (positive regulation of immune effector process), GO:0031347 (regulation of defense response), GO:0001961 (positive regulation of cytokine-mediated signaling pathway), GO:0006508 (proteolysis), GO:0001959 (regulation of cytokine-mediated signaling pathway), GO:0070269 (pyroptosis), GO:0002718 (regulation of cytokine production involved in immune response), GO:0051604 (protein maturation), GO:0010628 (positive regulation of gene expression), GO:0032652 (regulation of interleukin-1 production), GO:0010468 (regulation of gene expression), GO:0050727 (regulation of inflammatory response), GO:0050729 (positive regulation of inflammatory response), GO:0042742 (defense response to bacterium), GO:0032732 (positive regulation of interleukin-1 production), GO:0006996 (organelle organization), GO:0010467 (gene expression), GO:0097435 (supramolecular fiber organization), GO:0007015 (actin filament organization), GO:0002720 (positive regulation of cytokine production involved in immune response), GO:0010935 (regulation of macrophage cytokine production), GO:0061081 (positive regulation of myeloid leukocyte cytokine production involved in immune response), GO:0016485 (protein processing), GO:0032651 (regulation of interleukin-1 beta production), GO:0007010 (cytoskeleton organization), GO:0050830 (defense response to Gram-positive bacterium), GO:0032731 (positive regulation of interleukin-1 beta production), GO:0060907 (positive regulation of macrophage cytokine production), GO:0016540 (protein autoprocessing)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0032991 (protein-containing complex), GO:0005829 (cytosol), GO:0005622 (intracellular anatomical structure), GO:0061702 (inflammasome complex), GO:0005737 (cytoplasm)