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Details on Person Upon recognition of bacterial lipopolysaccharide (LPS), huma...
| Class:Id | Summation:9947854 |
|---|---|
| _displayName | Upon recognition of bacterial lipopolysaccharide (LPS), huma... |
| _timestamp | 2025-08-14 12:54:06 |
| created | [InstanceEdit:9947847] Shamovsky, Veronica, 2025-05-14 |
| literatureReference | [LiteratureReference:9947803] Caspase-4 dimerisation and D289 auto-processing elicit an interleukin-1β-converting enzyme [LiteratureReference:9710021] Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis [LiteratureReference:9647649] Inflammatory Caspases: Activation and Cleavage of Gasdermin-D In Vitro and During Pyroptosis [LiteratureReference:9652838] Inflammatory caspases are innate immune receptors for intracellular LPS [LiteratureReference:9647669] Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death [LiteratureReference:9947979] Structural insights into cytokine cleavage by inflammatory caspase-4 [LiteratureReference:9947810] Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome [LiteratureReference:9947923] Caspase-4 Activation and Recruitment to Intracellular Gram-Negative Bacteria [LiteratureReference:9686086] Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens [LiteratureReference:9958787] Inflammatory Caspases: Toward a Unified Model for Caspase Activation by Inflammasomes [LiteratureReference:9716215] Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling [LiteratureReference:9647685] Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores [LiteratureReference:9647674] Pore-forming activity and structural autoinhibition of the gasdermin family [LiteratureReference:9647662] GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death [LiteratureReference:9963522] GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes [LiteratureReference:9958631] The tetrapeptide sequence of IL-18 and IL-1β regulates their recruitment and activation by inflammatory caspases |
| modified | [InstanceEdit:9954296] Shamovsky, Veronica, 2025-06-06 [InstanceEdit:9958782] Shamovsky, Veronica, 2025-06-25 [InstanceEdit:9958785] Shamovsky, Veronica, 2025-06-25 [InstanceEdit:9960531] Shamovsky, Veronica, 2025-07-14 [InstanceEdit:9963571] Shamovsky, Veronica, 2025-08-14 [InstanceEdit:9963576] Shamovsky, Veronica, 2025-08-14 |
| text | Upon recognition of bacterial lipopolysaccharide (LPS), human pro-caspase-4 (CASP4) molecules are brought into close proximity, promoting CASP4 dimerization. In the dimeric state, the protease domains of the two inactive CASP4 monomers align in an antiparallel orientation. This dimerization induces conformational changes that expose the catalytic sites, enabling autocatalytic cleavage into smaller fragments. Biochemical analysis of LPS-activated human CASP4 purified from insect cells revealed four processed fragments, p31 (CASP4(1-270)), p24 (CASP4(60-270)), p12 (CASP4(271-377)), and p10 (CASP4(290-377)), which are generated through three autoprocessing events at aspartic acid residue 59 (D59), D270, and D289, as determined by N-terminal sequencing and mass spectrometry (Wang K et al., 2020). In this processing model, the large subunit corresponds to p31 (CASP4(1–270)) and the small subunit to p10 (CASP4(290–377)) (Wang K et al., 2020). The large and small subunits from each monomer then assemble into two p31:p10 heterodimers, which subsequently associate to form a 2x(CASP4(1–270):CASP4(290–377)) heterotetramer, the catalytically active form of CASP4 (Casson CN et al., 2015; Wang K et al., 2020; Chan AH et al., 2023; Shi X et al., 2023; Dilucca M & Broz P, 2023; reviewed by Ross C et al., 2022). Notably, cleavage at D289 is the only autoprocessing event essential for full CASP4 activation and the induction of pyroptosis (Wang K et al., 2020). Additionally, autoprocessing at D289 may generate a p33:p10 active CASP4 (Wang K et al., 2020; Chan AH et al., 2023). Once activated, caspase-4 (CASP4) cleaves gasdermin D (GSDMD), a substrate also targeted by CASP1, CASP4, and Casp11, a murine homolog of human CASP4 and CASP5 (Shi J et al., 2015; Kayagaki N et al., 2015; Zhao Y et al., 2018; Wang K et al., 2020; Downs KP et al., 2020). This cleavage releases the cytotoxic N-terminal fragment, GSDMD(1–275), which oligomerizes to form membrane pores and induce pyroptosis, while the C-terminal fragment, GSDMD(276–484), normally inhibits pore formation by binding the N-terminus (Shi J et al., 2015; Liu X et al., 2016; Ding J et al., 2016; Sborgi L et al., 2016; Aglietti RA et al., 2016; Liu Z et al., 2019; Yang J et al., 2018; Kuang S et al., 2017; Wang K et al., 2020). In addition, CASP4 efficiently cleaves pro-IL-18 at D36 to produce the mature, active cytokine, a process driven by a unique bivalent recognition mechanism involving both a protease exosite and the active site. In contrast, CASP4-mediated cleavage of pro-IL-1β, occurring primarily at D27, yields an inactive fragment, with less efficient processing observed at D116, the canonical pro-IL-1β activation site (Shi X et al., 2023; Devant P et al., 2023; Exconde PM et al., 2023; Chan AH et al., 2023). |
| (summation) | [Reaction:9947908] CASP4 autocatalysis on the bacterial surface [Homo sapiens] |
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