title: 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.
authors.affiliation: *Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing 210061, China.
authors.forename: Peiliang
authors.initials: P
authors.lastname: Shi
authors.affiliation: *Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing 210061, China.
authors.forename: An
authors.initials: A
authors.lastname: Tang
authors.affiliation: *Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing 210061, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xian
authors.affiliation: *Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing 210061, China.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Hou
authors.affiliation: *Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing 210061, China.
authors.forename: Dayuan
authors.initials: D
authors.lastname: Zou
authors.affiliation: †Department of Cell Biology and Medical Genetics, Research Center for Molecular Medicine, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310000, China.
authors.forename: Yasu
authors.initials: Y
authors.lastname: Lv
authors.affiliation: *Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing 210061, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Huang
authors.affiliation: *Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing 210061, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
authors.affiliation: *Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing 210061, China.
authors.forename: Anying
authors.initials: A
authors.lastname: Song
authors.affiliation: *Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing 210061, China.
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Lin
authors.affiliation: *Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Collaborative Innovation Center of Genetics and Development, Nanjing University, Nanjing 210061, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
mesh_terms: D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D016923:Cell Death; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011506:Proteins / Q000502:physiology*; D017382:Reactive Oxygen Species; D000094524:Gasdermins
chemical_list: D011506:Proteins; D017382:Reactive Oxygen Species; C499121:Gsdma3 protein, mouse; D000094524:Gasdermins