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Details on Person Activation of the inflammatory caspase‑4 (CASP4) is induced ...
| Class:Id | Summation:9710103 |
|---|---|
| _displayName | Activation of the inflammatory caspase‑4 (CASP4) is induced ... |
| _timestamp | 2025-08-14 10:08:32 |
| created | [InstanceEdit:9710120] Shamovsky, Veronica, 2020-12-25 |
| literatureReference | [LiteratureReference:9647617] Crystal Structures of the Full-Length Murine and Human Gasdermin D Reveal Mechanisms of Autoinhibition, Lipid Binding, and Oligomerization [LiteratureReference:9647628] Structure insight of GSDMD reveals the basis of GSDMD autoinhibition in cell pyroptosis [LiteratureReference:9647674] Pore-forming activity and structural autoinhibition of the gasdermin family [LiteratureReference:9647624] Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor [LiteratureReference:9647669] Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death [LiteratureReference:9647670] Mechanisms of Gasdermin Family Members in Inflammasome Signaling and Cell Death [LiteratureReference:9647662] GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death [LiteratureReference:9710125] The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages [LiteratureReference:9710113] An overview of the non-canonical inflammasome [LiteratureReference:9710108] A critical role for human caspase-4 in endotoxin sensitivity [LiteratureReference:9710086] Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways [LiteratureReference:9686086] Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens [LiteratureReference:9710021] Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis [LiteratureReference:9686131] Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes [LiteratureReference:9716215] Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling [LiteratureReference:9652838] Inflammatory caspases are innate immune receptors for intracellular LPS [LiteratureReference:9728814] Innate immunity to intracellular LPS [LiteratureReference:9710235] Cryo-EM structure of the gasdermin A3 membrane pore [LiteratureReference:9963525] Gasdermin D pore structure reveals preferential release of mature interleukin-1 [LiteratureReference:9647685] Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores [LiteratureReference:9963522] GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes [LiteratureReference:9728819] The gasdermins, a protein family executing cell death and inflammation [LiteratureReference:9963529] Channelling inflammation: gasdermins in physiology and disease |
| modified | [InstanceEdit:9711033] Shamovsky, Veronica, 2021-01-07 [InstanceEdit:9716212] Shamovsky, Veronica, 2021-02-19 [InstanceEdit:9728815] Shamovsky, Veronica, 2021-04-22 [InstanceEdit:9963520] Shamovsky, Veronica, 2025-08-14 |
| text | Activation of the inflammatory caspase‑4 (CASP4) is induced upon sensing of intracellular bacterial lipopolysaccharide (LPS) (Shi J et al. 2014; Kajiwara Y et al. 2014; Casson CN et al. 2015; Vigano E et al. 2015; Lagrange B et al. 2018). Activated CASP4 drives non‑canonical inflammasome responses to fight bacterial infections (reviewed in Rathinam VAK et al. 2019; Zamyatina A & Heine H 2020; Downs KP et al. 2020). LPS triggers auto‑processing at D289 in the inter‑subunit linker of CASP4, generating a CASP4 subunit p10 (290‑377) (Wang K et al. 2020). The CASP4 autoprocessing at D289 was required for induction of gasdermin D (GSDMD) cleavage thus promoting pyroptosis in human CASP4‑/‑ epidermoid carcinoma A431 and HeLa cells that stably expressed Flag‑tagged CASP4 (Wang K et al. 2020). Human CASP5 is thought to function similarly to CASP4 (Vigano E et al. 2015; Shi J et al. 2015). The protease activity of CASP5 can initiate pyroptosis through processing of GSDMD at D275, which is covered by this Reactome annotation. However, the mechanisms underlying activation and LPS recognition by CASP5 require further study. Further, structural studies suggest that binding of GSDMD to CASP4 allosterically enhanced the catalytic activity of CASP4 by stabilizing the dimeric form of processed CASP4 (2xp10:p20) (Wang K et al. 2020). Once activated, CASP4, CASP5 cleave GSDMD at D275 within the central linker region generating a 31‑kDa N‑terminal fragment (GSDMD (1‑275)) which has an intrinsic pore‑forming activity to initiate pyroptosis and a 22‑kDa C‑terminal fragment (GSDMD (276‑484)) which inhibits cell death through intramolecular domain association (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; Kuang S et al. 2017; Feng S et al., 2018; Yang J et al. 2018; Liu Z et al. 2019). The expression of GSDMD (1-275) but not the C-terminal fragment of GSDMD (276-484) induced pyroptosis in human embryonic kidney 293 (HEK293) cells (Shi J et al. 2015). In addition, biochemical and structural studies of human GSDMD and mouse GSDMA3 showed the auto‑inhibitory conformation of gasdermin domains which is released upon interdomain cleavage by inflammatory caspases, including CASP4 (Shi J et al. 2015; Ding J et al. 2016; Liu Z et al. 2019; Yang J et al. 2018; Kuang S et al. 2017; Ruan J et al., 2018; Xia S et al., 2021). Thus, the CASP4-, CASP5‑mediated cleavage is thought to release the cytotoxic GSDMD (1‑275) from intramolecular autoinhibition mediated by the C‑terminal fragment of GSDMD. The N‑terminal domain of GSDMD (1‑275) binds and inserts into lipid membranes where it assembles into pores 10‑16 nm in diameter (Liu X et al., 2016; Ding J et al. 2016; Sborgi L et al. 2016; Aglietti RA et al., 2016; Feng S et al., 2018; Xia S et al., 2021). GSDMD pores facilitate the secretion of active forms of interleukin‑1β (IL‑1β) and IL‑18 from pyroptotic cells (Shi J et al. 2015; Ding J et al. 2016; Evavold CL et al. 2018; reviewed by Broz P et al., 2020; Liu X et al., 2021)). "The increasing abundance of membrane pores ultimately leads to membrane rupture and pyroptosis, releasing the entire cellular content" ‑ Feng S et al. 2018. The murine homolog of CASP4/5, CASP11, can also cleave GSDMD (Shi J et al. 2015; Kayagaki N et al. 2015). This Reactome event shows CASP4/CASP5‑mediated cleavage of GSDMD at D275. |
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