The epidermis forms a critical physical and immune barrier, which could be compromised by deregulated responses of keratinocyte to external stimuli and ensuing inappropriate cell death. GASDERMIN A (GSDMA) was involved in gastric epithelial apoptosis and has been implicated in airway hyperresponsiveness. Its function in the skin was indicated by dominant mutations in gasdermin A3 (Gsdma3), which caused inflammation-mediated epidermal hyperplasia and hair loss in mice. The mechanisms of Gsdma3’s action and pathogenesis are unknown. Here, we showed that Gsdma3 is regulated by intramolecular fold-back inhibition, which is disrupted by dominant mutations in the C-terminal domain. The unmasked N-terminal domain of Gsdma3 then associates with Hsp90 and is delivered to mitochondrial via the mitochondrial import receptor Tom70, where it interacts with the mitohcondrial chaperone Trap1 and causes oxidative stress-mediated mitochondrial permeability transition and caspase-independent cell death. Using an inducible transgenic mouse model, we demonstrated that epidermis-specific expression of Gsdma3 caused spontaneous keratinocyte necrosis and sterile skin inflammation in vivo. In primary keratinocytes isolated from the transgenic mice, Gsdma3 expression caused mitochondrial oxidative stress and necrosis. We hypothesized that Gsdma3 functions as a stress sensor, which regulates the susceptibility of keratinocytes to necrosis and its deregulation leads to chronic inflammatory skin diseases.
Date:
2015-05
Relation:
Journal of Investigative Dermatology. 2015 May;135(S1):S75.
