lmmol · Proteins

Caspase-4

UniProt P70343 Organism Mus musculus Gene Casp11, Casp4, Caspl, Ich3 EC 3.4.22.64

Also known as: Casp11, Casp4, Caspl, Ich3

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.

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
Cytochrome P450 & Heme Enzymes

Experimental structures · PDB · 5

A predicted model is available from AlphaFold.

Gene Ontology · 33

Neighborhood · nearest proteins

Casp11Casp12Casp12Caspase-12CASP4GsdmdIgif
Nearest neighbours of Caspase-4: 3 by sequence/function similarity (left); 3 co-cited in the literature (right).

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

Literature · 32 cited papers

A document in the lmmol reference corpus — open public data (UniProt, GO, PDB, the literature graph) rendered as a single cross-linked page. Hover any link to preview its target.