Reactome | GSDME (1-270) binds cardiolipin

GSDME (1-270) binds cardiolipin

Stable Identifier

R-HSA-9710354

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol, mitochondrial outer membrane

ReviewStatus

5/5

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Gasdermin E (GSDME) is cleaved by caspase 3 (CASP3) at D270 in response to apoptotic stimuli (Rogers C et al. 2017; Wang Y et al. 2017). The released N‑terminal fragment of GSDME (1‑270) targets the plasma membrane to drive pyroptosis in GSDME‑expressing cells (Wang Y et al. 2017). In addition, the N‑terminal fragment of mouse GSDME binds to cardiolipin liposomes causing severe leakage (Wang Y et al. 2017). Although cardiolipin is primarily located in the inner mitochondrial membrane, the outer mitochondrial membrane also contains around 10‑20% cardiolipin and cardiolipin translocates in a regulatable manner between the compartments (Liu J et al. 2003; reviewed in Dudek J 2017). Confocal microscopy and biochemical analysis revealed that tagged‑GSDME (1‑270) localized to mitochondria and triggered release of proapoptotic proteins such as cytochrome c (CYCS) upon ectopic expression in human HeLa cells or human embryonic kidney 293T (HEK293T) cells (Rogers C et al. 2019). Endogenous GSDME (1‑270) also localized to the mitochondrial fraction during apoptosis in TNFα plus actinomycin D (TNFα/actD)‑treated human lymphoid CEM‑C7 cells. Apoptotic stimuli‑triggered cleavage of GSDME (1‑270) induced CYCS release and ROS production in CEM‑C7 cells (Rogers C et al. 2019). These data suggest that the N‑terminal fragment of GSDME (1‑270) can permeabilize the mitochondria in response to apoptotic stimuli (Rogers C et al. 2019), however, the physiological relevance of this event remains to be determined.

This Reactome event describes the GSDME (1‑275) binding to mitochondrial cardiolipin leading to CYCS release from the mitochondria.

Literature References

PubMed ID	Title	Journal	Year
29898893	Mechanism of membrane pore formation by human gasdermin-D Pfreundschuh, M, Mari, SA, Sborgi, L, Hiller, S, Müller, DJ, Mulvihill, E	EMBO J.	2018
30976076	Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation Nardone, A, Aplin, AE, Rogers, C, Erkes, DA, Alnemri, ES, Fernandes-Alnemri, T	Nat Commun	2019
27281216	Pore-forming activity and structural autoinhibition of the gasdermin family Wang, DC, Ding, J, Liu, W, Shi, J, Shao, F, Wang, K, Sun, Q, Sun, H, She, Y	Nature	2016