CASP1 cleaves GSDMD

Stable Identifier
R-HSA-9647680
Type
Reaction [omitted]
Species
Homo sapiens
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Inflammatory caspase‑1 (CASP1) is activated within the canonical inflammasome, a multiprotein complex assembled in response to sensing of pathogen‑derived particles or host‑derived danger signals (reviewed in Kelley N et al. 2019; Zheng D et al. 2020). Activated, CASP1 cleaves gasdermin D (GSDMD) 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; Ding J et al. 2016; Sborgi L et al. 2016; Liu Z et al. 2019; Yang J et al. 2018; Kuang S et al. 2017). The expression of GSDMD (1‑275) in human embryonic kidney 293 (HEK293) cells induced pyroptosis (Shi J et al. 2015). The catalytic domain of CASP1 was found to directly bind to GSDMD or its cleavage site peptide, FLTD (Yang J et al. 2018). A GSDMD‑derived inhibitor, N‑acetyl‑Phe‑Leu‑Thr‑Asp‑chloromethylketone (Ac‑FLTD‑CMK), inhibited GSDMD cleavage in vitro and suppressed pyroptosis downstream of both canonical and noncanonical inflammasomes. The structure of human CASP1 in complex with Ac‑FLTD‑CMK revealed extensive enzyme–inhibitor interactions involving both hydrogen bonds and hydrophobic contacts (Yang J et al. 2018). 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 CASP1 (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; reviewed in Orning P et al. 2019). Thus, the CASP1‑mediated cleavage is thought to release the cytotoxic GSDMD (1‑275) from intramolecular autoinhibition by the C‑terminal fragment of GSDMD. The N‑terminal domain GSDMD (1‑275) binds and inserts into lipid membranes where it assembles into pores 10‑16 nm in diameter (Ding J et al. 2016; Sborgi L et al. 2016). GSDMD pores facilitate the secretion of active forms of interleukin‑1β (IL‑1β) and IL‑18 from pyroptotic cells (Shi J et al. 2015; He W et al. 2015; Ding J et al. 2016; Evavold CL et al. 2018). "The increasing abundance of membrane pores ultimately leads to membrane rupture and pyroptosis, releasing the entire cellular content" ‑ Feng S et al. 2018.

This Reactome event shows CASP1‑mediated cleavage of GSDMD at D275.

Literature References
PubMed ID Title Journal Year
26375003 Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death

Shi, J, Zhao, Y, Wang, K, Shi, X, Wang, Y, Huang, H, Zhuang, Y, Cai, T, Wang, F, Shao, F

Nature 2015
29891674 Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor

Yang, J, Liu, Z, Wang, C, Yang, R, Rathkey, JK, Pinkard, OW, Shi, W, Chen, Y, Dubyak, GR, Abbott, DW, Xiao, TS

Proc. Natl. Acad. Sci. U.S.A. 2018
29177860 Inflammatory Caspases: Activation and Cleavage of Gasdermin-D In Vitro and During Pyroptosis

Zhao, Y, Shi, J, Shao, F

Methods Mol. Biol. 2018
32109412 Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis

Wang, K, Sun, Q, Zhong, X, Zeng, M, Zeng, H, Shi, X, Li, Z, Wang, Y, Zhao, Q, Shao, F, Ding, J

Cell 2020
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Catalyst Activity

cysteine-type endopeptidase activity of Caspase-1 tetramer [cytosol]

This event is regulated
Orthologous Events
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