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.
Loss of function of GSDME variant [cytosol]