Loss of conserved Gsdma3 self-regulation causes autophagy and cell death

Abstract

Gasdermin A3 (Gsdma3) was originally identified in association with hair-loss phenotype in mouse mutants. Our previous study found that AE mutant mice, with a Y344H substitution at the C-terminal domain of Gsdma3, display inflammation-dependent alopecia and excoriation [Zhou et al. (2012) Am. J. Pathol. 180, 763-774]. Interestingly, we found that the newly-generated null mutant of Gsdma3 mice did not display the skin dysmorphology, indicating that Gsdma3 is not essential for differentiation of epidermal cells and maintenance of the hair cycle in normal physiological conditions. Consistently, human embryonic kidney (HEK)293 and HaCaT cells transfected with wild-type (WT) Gsdma3 did not show abnormal morphology. However, Gsdma3 Y344H mutation induced autophagy. Gsdma3 N-terminal domain, but not the C-terminal domain, also displayed the similar pro-autophagic activity. The Gsdma3 Y344H mutant protein and N-terminal domain-induced autophagy was associated with mitochondria and ROS generation. Co-expression of C-terminal domain reversed the cell autophagy induced by N-terminal domain. Moreover, C-terminal domain could be co-precipitated with N-terminal domain. These data indicated that the potential pro-autophagic activity of WT Gsdma3 protein is suppressed through an intramolecular inhibition mechanism. Studies on other members of the GSDM family suggested this mechanism is conserved in several sub-families.

Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein

“…Subsequent reports confirmed the binding of GSDMD_N to PtdIns(4)P, PtdIns(3,4)P 2 , phosphatidic acid, and cardiolipin, and weakly to phosphatidylserine (32). Because cardiolipin is a component of the inner leaflet of mitochondrial membrane, the binding data substantiated previous results that Gsdma3 is transported into the mitochondria to disrupt mitochondrial membranes (26,27) although mitochondrial localization was not reported for GSDMD. For GSDMD, phospholipid binding enables higher order oligomerization of the GSDMD N-terminal domain in the lipid bilayer and formation of ring structure-like pores to disrupt membrane structure.…”

“…Recent reports identified the N-terminal domain of mouse Gsdma3, expressed in HEK293 and HaCatT cells, as well as Gsdma3 mutants that cause skin and hair defects in mice, to promote cell death (26,27). Similarly, the N-terminal domains of human GSDMA, GSDMC, and GSDMD caused autophagy whereas the cells remain viable in the presence of the respective C-terminal domains (27).…”

“…Interestingly, coimmunoprecipitation experiments identified the binding of GSDMB to HSP90β in breast cancer cells (8). The N-terminal domain of GSDMB did not induce autophagy (27),…”

“…Similarly, the N-terminal domains of human GSDMA, GSDMC, and GSDMD caused autophagy whereas the cells remain viable in the presence of the respective C-terminal domains (27). For Gsdam3, the autophagy is initiated when the N-terminal domain binds to heat shock protein 90 (HSP90), and the complex is delivered to the mitochondria by the HSP90/HSP70/ Hop complex via the Tom70 importer (26).…”

Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases

“…This finding suggests that other undefined caspase-1 substrates must also contribute to caspase-1-dependent pyroptosis (25). It is noteworthy to highlight that other members of the gasdermin family can also induce cell death, including mouse gasdermin A3, human gasdermin A, human gasdermin B, human gasdermin C and human and mouse DFNA5 (27, 96–98). Whether these proteins have a role in inflammasome signaling, pyroptosis or in host defense against pathogens remains to be determined.…”