Caspase-4

The CARD domain mediates LPS recognition and homooligomerization.

Inflammatory caspase that acts as the effector of the non-canonical inflammasome by mediating lipopolysaccharide (LPS)-induced pyroptosis (PubMed:22002608, PubMed:23348507, PubMed:23887873, PubMed:24031018, PubMed:25119034, PubMed:30135078, PubMed:37001519, PubMed:38632402). Also indirectly activates the NLRP3 and NLRP6 inflammasomes (PubMed:26320999, PubMed:30392956, PubMed:37001519). Acts as a thiol protease that cleaves a tetrapeptide after an Asp residue at position P1: catalyzes cleavage of CGAS and GSDMD (PubMed:26375003, PubMed:28314590, PubMed:30392956, PubMed:38632402). In contrast to its human ortholog, does not cleave IL18 (PubMed:37993712, PubMed:37993714). 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 (PubMed:22002608, PubMed:22895188, PubMed:23348507, PubMed:23887873, PubMed:24031018, PubMed:26320999, PubMed:26375003, PubMed:30135078, PubMed:30589883). 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 (PubMed:22002608, PubMed:23348507, PubMed:25119034, PubMed:37001519, PubMed:38632402). 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 (PubMed:22002608, PubMed:23348507, PubMed:25119034, PubMed:38632402). 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 (PubMed:26320999). 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 (PubMed:30392956). 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 (PubMed:23348507). Plays a crucial role in the restriction of S.typhimurium replication in colonic epithelial cells during infection (PubMed:25121752, PubMed:26375003, PubMed:34671164). Activation of the non-canonical inflammasome in brain endothelial cells can lead to excessive pyroptosis, leading to blood-brain barrier breakdown (PubMed:38632402). Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation (PubMed:25121752). 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) (PubMed:27103670). 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 (PubMed:32109412, PubMed:32554464). In contrast, it does not directly process IL1B (PubMed:8702803, PubMed:9038361). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590).

In response to activation signals, undergoes autoproteolytic cleavage and activation.

(Microbial infection) ADP-riboxanation by S.flexneri OspC3 blocks CASP4 autoprocessing, preventing CASP4 activation and ability to recognize and cleave GSDMD, thereby thwarting the inflammasome/pyroptosis-mediated defense.

Belongs to the peptidase C14A family.

Widely expressed, including in thymus, lung and spleen (at protein level). Very low levels, if any, in the brain.

• Cytoplasm
• Cytosol
• Cytoplasm
• Endoplasmic reticulum membrane
• Peripheral membrane protein
• Cytoplasmic side
• Mitochondrion
• Inflammasome
• Secreted
• Predominantly localizes to the endoplasmic reticulum (ER). Association with the ER membrane requires TMEM214. Released in the extracellular milieu by keratinocytes following UVB irradiation.

Casp11, Caspl, Ich3, Casp4, Caspase-4, CASP-4, Caspase-11, Protease ICH-3, CASP-11

• entrezGene:12363
• swissprot:P70343

Proteins

Immunology & Infectious Disease

42742Da