Loss of Conserved Gsdma3 Self-Regulation Causes Autophagy and Cell Death

Gsdermin A3 (Gsdma3) was originally identified for associating with hair-loss phenotype in mouse mutants. Our previous study found AE mutant mice, with a Y344H substitution at C-terminal domain of Gsdma3, display inflammation-dependent alopecia and excoriation. 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 innormal physiological conditions. Consistently, HEK293 and HaCaT cells transfected with wild-type 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 revised 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 wild-type 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.

Source: BJ Disease - March 31, 2015 Category: Biochemistry Authors: P Shi, A Tang, L Xian, S Hou, D Zou, Y Lv, Z Huang, Q Wang, A Song, Z Lin, X Gao Tags: BJ Disease Source Type: research