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Details on Person Caspase-5 (CASP5), an inflammatory caspase closely related t...
| Class:Id | Summation:9958656 |
|---|---|
| _displayName | Caspase-5 (CASP5), an inflammatory caspase closely related t... |
| _timestamp | 2025-08-21 13:03:38 |
| created | [InstanceEdit:9958641] Shamovsky, Veronica, 2025-06-24 |
| literatureReference | [LiteratureReference:9958666] Identification of a novel exon encoding the amino-terminus of the predominant caspase-5 variants [LiteratureReference:9958651] Expression analysis of the human caspase-1 subfamily reveals specific regulation of the CASP5 gene by lipopolysaccharide and interferon-gamma [LiteratureReference:9958643] Caspase-5: Structure, Pro-Inflammatory Activity and Evolution [LiteratureReference:9647669] Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death [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:9686131] Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes [LiteratureReference:9958640] Type-I interferon shapes peritoneal immunity in cirrhosis and drives caspase-5-mediated progranulin release upon infection [LiteratureReference:9958634] Caspase-11 contributes to site-1 protease cleavage and SREBP1 activation in the inflammatory response of macrophages [LiteratureReference:9958631] The tetrapeptide sequence of IL-18 and IL-1β regulates their recruitment and activation by inflammatory caspases [LiteratureReference:9947798] High-affinity caspase-4 binding to LPS presented as high molecular mass aggregates or in outer membrane vesicles [LiteratureReference:9947828] Membrane vesicles from Pseudomonas aeruginosa activate the noncanonical inflammasome through caspase-5 in human monocytes [LiteratureReference:9947825] Detecting lipopolysaccharide in the cytosol of mammalian cells: Lessons from MD-2/TLR4 [LiteratureReference:9947805] The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation [LiteratureReference:9948009] Guanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platforms [LiteratureReference:9947948] Human GBP1 binds LPS to initiate assembly of a caspase-4 activating platform on cytosolic bacteria [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:9958663] Inflammatory caspase substrate specificities [LiteratureReference:9947810] Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome |
| modified | [InstanceEdit:9958782] Shamovsky, Veronica, 2025-06-25 [InstanceEdit:9958785] Shamovsky, Veronica, 2025-06-25 [InstanceEdit:9960503] Shamovsky, Veronica, 2025-07-14 [InstanceEdit:9960548] Shamovsky, Veronica, 2025-07-14 [InstanceEdit:9963549] Shamovsky, Veronica, 2025-08-14 [InstanceEdit:9963576] Shamovsky, Veronica, 2025-08-14 [InstanceEdit:9963583] Shamovsky, Veronica, 2025-08-14 [InstanceEdit:9964257] Shamovsky, Veronica, 2025-08-21 |
| text | Caspase-5 (CASP5), an inflammatory caspase closely related to caspase-4, is involved in the innate immune response triggered by cytosolic lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria (Shi J et al., 2014, 2015; reviewed by Eckhart L & Fischer H, 2024). CASP5 expression is low at baseline but strongly induced by pro-inflammatory stimuli such as LPS through TLR4-dependent NF-κB signaling (Lin XY et al., 2000; Eckhart L et al., 2006; Viganò E et al., 2015). In human peripheral blood mononuclear cells (PBMCs), LPS stimulation results in a >10-fold increase in CASP5 expression levels, a greater induction than that observed for CASP1 or CASP4 (Eckhart L et al., 2006). Similarly, CASP5 shows higher LPS-inducibility in human monocytes at both mRNA and protein levels compared to CASP4 (Viganò E et al., 2015; Cheng Y et al., 2023). Both interferon γ (IFNγ) and IFNα/β may contribute to CASP5 upregulation by activating JAK-STAT-dependent transcription (Lin XY et al., 2000; Eckhart L et al., 2006; Rooney M et al., 2024). Promoter analysis reveals conserved NF-κB and STAT binding motifs (Eckhart L et al., 2006), and expression is highest in immune-related tissues including blood, spleen, lung, and colon, as per GTEx data (Eckhart L & Fischer H 2024). CASP5, like CASP4, is activated when intracellular bacterial LPS binds to its N-terminal caspase activation and recruitment domain (CARD), promoting oligomerization and proximity-induced activation of CASP5 (Shi J et al., 2014). CASP5 undergoes autocatalytic cleavage at aspartate residues, yielding large and small subunits that assemble into the active CASP5 heterotetramer (Shi J et al., 2014; Viganò et al., 2015). Activated CASP5 can then cleave gasdermin D (GSDMD), which is also a substrate of CASP1, CASP4, and Casp11, a murine homolog of human CASP4/CASP5 (Shi J et al., 2014, 2015; Kayagaki N et al., 2015; Zhao Y et al., 2018; Wang K et al., 2020). The resulting N-terminal fragment of GSDMD oligomerizes to form pores in the cell membrane, leading to pyroptosis in mammals (Liu X et al., 2016; Ding J et al., 2016; Sborgi L et al., 2016; Aglietti RA et al., 2016). CASP5 also processes pro-IL-18 and pro-IL-1β. Like CASP4, CASP5 efficiently cleaves pro-interleukin-18 (pro-IL-18) at aspartic acid residue D36 to generate its mature, biologically active form (Shi X et al., 2023; Devant P et al., 2023; Exconde PM et al., 2023; reviewed by Exconde PM, 2024). Structural and biochemical analyses revealed that this cleavage relies on a bivalent recognition mechanism, in which pro-IL-18 binds CASP4/CASP5 through two interfaces: the protease exosite binds a hydrophobic pocket within pro-IL-18, while the active site of caspase engages charged residues located within and adjacent to the tetrapeptide recognition motif in the pro-domain (Shi X et al., 2023; Devant P et al., 2023). In contrast, CASP5- and CASP4-mediated cleavage of pro-IL-1β at D27 produces an inactive fragment that lacks receptor-stimulating activity (Exconde PM et al., 2023; reviewed by Exconde PM, 2024). Cytosolic delivery of LPS can occur via endocytosis of outer membrane vesicles (OMVs) released by Gram-negative bacteria (Wacker MA et al., 2017; Bitto NJ et al., 2018; reviewed in Barker JH and Weiss JP, 2019; Page MJ et al., 2022), or through phagolysosomal rupture following bacterial uptake. Guanylate-binding protein 1 (GBP1) directly binds LPS on cytosol-exposed bacteria and, along with other GBPs (GBP2, GBP3 and GBP4, forms a coat on the bacterial surface, creating a platform that recruits CASP4 to facilitate inflammasome activation (Santos JC et al., 2020; Wandel MP et al., 2020). While CASP5 likely follows a similar GBP-mediated recruitment mechanism, there is currently no direct evidence for a physical interaction between CASP5 and GBPs, and this interaction is therefore not shown here. |
| (summation) | [Pathway:9948011] CASP5 inflammasome assembly [Homo sapiens] |
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