Reactome | ELANE cleaves GSDMD

ELANE cleaves GSDMD

Stable Identifier

R-HSA-9710106

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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In neutrophils, gasdermin D (GSDMD) is cleaved by the serine protease, neutrophil elastase (NE or ELANE), which is released from the granules to cytosol during formation of neutrophil extracellular traps (NET) (Sollberger G et al. 2018; Kambara H et al. 2018). The process of NET formation and NET release is called NETosis, a programmed neutrophil cell death, which is induced in response to microbial infection and endogenous danger signals (reviewed in Papayannopoulos V 2018; Vorobjeva NV & Chernyak BV 2020). NETosis is characterized by the release of granule components such as ELANE or MPO into the cytosol, as well as chromatin decondensation associated with histone modification (reviewed in Papayannopoulos V 2018; Vorobjeva NV & Chernyak BV 2020). Although NETs may protect the host against microbes, excessive NET formation can contribute to the pathogenesis of immune‑related diseases (reviewed in Papayannopoulos V 2018; Mutua V & Gershwin LJ 2020).

The cleavage of GSDMD by human neutrophil lysate was inhibited by ELANE‑specific inhibitors in a dose‑dependent manner (Kambara H et al. 2018). The identified ELANE cleavage site C268 in human GSDMD is different from the caspase cleavage site D275 and is not conserved between humans and mice (Kambara H et al. 2018). The N‑terminal fragment of GSDMD (1‑268) formed oligomers and induced lytic cell death upon overexpression in human embryonic kidney HEK293 cells (Kambara H et al. 2018). High‑resolution total internal reflection fluorescence (TIRF) microscopy showed that after NET formation GSDMD localized to the plasma membrane in human primary neutrophils (Sollberger G et al. 2018). These data suggest that GSDMD cleavage by ELANE at D268 induces lytic cell death in neutrophils (Sollberger G et al. 2018; Kambara H et al. 2018). In addition, the N‑terminal fragment of GSDMD was shown to target azurophilic (primary) granules and autophagosomes in human and murine neutrophils (Karmakar M et al. 2020). In this study the N‑terminal fragment of GSDMD facilitated release of ELANE into the cytosol by permeabilization of azurophilic granules and secretion of IL‑1β via an autophagy machinery‑dependent pathway (Karmakar M et al. 2020).

Literature References

PubMed ID	Title	Journal	Year
29539421	Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death Xu, Y, Bajrami, B, Han, M, Zhang, X, Zhou, S, Liu, P, Teng, Y, Silberstein, LE, Zhao, L, Cheng, T, Luo, HR, Liu, F, Yu, H, Zhou, W, Kambara, H	Cell Rep	2018
30143555	Gasdermin D plays a vital role in the generation of neutrophil extracellular traps Nussbaumer, P, Herzig, A, Habenberger, P, Eickhoff, J, Klebl, B, Menninger, S, Choidas, A, Kordes, S, Di Lucrezia, R, Sollberger, G, Zychlinsky, A, Krüger, R, Burn, GL	Sci Immunol	2018