Reactome | CASP5 cleaves IL18 at D36

CASP5 cleaves IL18 at D36

Stable Identifier

R-HSA-9947978

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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Similar to CASP4, CASP5 efficiently cleaves pro-interleukin-18 (pro-IL-18) at aspartic acid residue D36, producing the mature, biologically active cytokine (Shi X et al., 2023; Devant P et al., 2023; Exconde PM et al., 2023, 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). The mature IL-18 cytokine is released through gasdermin D (GSDMD) pores, amplifying the inflammatory response in mammals (Shi J et al., 2015; Kayagaki N et al., 2015; reviewed by Broz P et al., 2020; Liu X et al., 2021).

Literature References

PubMed ID	Title	Journal	Year
37993712	Structural insights into cytokine cleavage by inflammatory caspase-4 Devant, P, Dong, Y, Mintseris, J, Ma, W, Gygi, SP, Wu, H, Kagan, JC	Nature	2023
37993714	Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome Shi, X, Sun, Q, Hou, Y, Zeng, H, Cao, Y, Dong, M, Ding, J, Shao, F	Nature	2023
38103201	The tetrapeptide sequence of IL-18 and IL-1β regulates their recruitment and activation by inflammatory caspases Exconde, PM, Hernandez-Chavez, C, Bourne, CM, Richards, RM, Bray, MB, Lopez, JL, Srivastava, T, Egan, MS, Zhang, J, Yoo, W, Shin, S, Discher, BM, Taabazuing, CY	Cell Rep	2023