CASP1 cleaves GSDMD

Stable Identifier
R-HSA-9647680
Type
Reaction [omitted]
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
General
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

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 execute pyroptosis and a 22‑kDa C‑terminal fragment (GSDMD (276‑484)) which otherwise 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). The most critical element determining the specific targeting of GSDMD by CASP1 as well as CASP4/5 and mouse Casp11 is a hydrophobic surface on the C‑terminal fragment (GSDMD (276‑484)) that is recognized by a short two-stranded β sheet at the dimer interface of the caspases, which leads to an unconventional tetrapeptide (cleavage-site sequence)-independent cleavage of GSDMD (Wang K et al. 2020; Liu Z et al. 2020). 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 contents" ‑ Feng S et al. 2018.

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

Literature References
PubMed ID Title Journal Year
29891674 Mechanism of gasdermin D recognition by inflammatory caspases and their inhibition by a gasdermin D-derived peptide inhibitor

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

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

Shi, J, Shao, F, Zhao, Y

Methods Mol. Biol. 2018
26375003 Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death

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

Nature 2015
32109412 Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis

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

Cell 2020
Participants
Participates
Catalyst Activity

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

This event is regulated
Orthologous Events
Authored
Reviewed
Created
Cite Us!