GSDME variant does not bind PIPs

Stable Identifier
R-HSA-9710468
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Cancer‑related loss of function (LOF) mutations in the N‑terminal fragment (1‑270) of gasdermin E (GSDME), i.e. the pore forming domain responsible for pyroptosis execution, reduced lactate dehydrogenase (LDH) release upon expression in human embryonic kidney 293T (HEK293T) cells (Zhang Z et al. 2020). The data suggest that GSDME missense variants and truncated mutants (W46*, E210*) with the disrupted N‑terminus cannot mediate pyroptosis, which is consistent with the known role of this region of GSDMD in pyroptosis.

The Reactome event shows the defective binding of GSDME variants to the cell membrane. However, there is no evidence suggesting those mutants bind or fail to bind PIPs. It is likely that many of these GSDME variants disrupt the oligomerization of GSDME. For example, D18V, N24D and P212L, which dramatically reduce GSDME pyroptosis, all disrupt the oligomerization interface according to a modeled GSDME structure (Zhang Z et al. 2020). Further studies are needed to elucidate the mechanisms underlying protein dysfunction of cancer‑associated LOF variants of GSDME.

Literature References
PubMed ID Title Journal Year
32188940 Gasdermin E suppresses tumour growth by activating anti-tumour immunity

Zhang, Z, Zhang, Y, Xia, S, Kong, Q, Li, S, Liu, X, Junqueira, C, Meza-Sosa, KF, Mok, TMY, Ansara, J, Sengupta, S, Yao, Y, Wu, H, Lieberman, J

Nature 2020
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Normal reaction
Functional status

Loss of function of GSDME variant [cytosol]

Status
Disease
Name Identifier Synonyms
breast carcinoma DOID:3459 Mammary carcinoma, carcinoma of breast
gastric adenocarcinoma DOID:3717 adenocarcinoma of stomach (disorder), stomach adenocarcinoma
lung adenocarcinoma DOID:3910 nonsmall cell adenocarcinoma
colon adenocarcinoma DOID:234 adenocarcinoma of the colon, adenocarcinoma of colon, Colonic adenocarcinoma
melanoma DOID:1909 Naevocarcinoma, melanoma, melanoma, malignant melanoma, morphology (morphologic abnormality), malignant melanoma NOS (morphologic abnormality), malignant melanoma (disorder), malignant melanoma, malignant melanoma, malignant melanoma, malignant melanoma
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
head and neck squamous cell carcinoma DOID:5520 carcinoma of the head and neck, squamous cell carcinoma of the head and neck
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