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.
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Research Article|
May 22 2015
Loss of conserved Gsdma3 self-regulation causes autophagy and cell death
Peiliang Shi;
Peiliang Shi
1
*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
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An Tang;
An Tang
1
*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
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Li Xian;
Li Xian
1
*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
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Siyuan Hou;
Siyuan Hou
*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
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Dayuan Zou;
Dayuan Zou
*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
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Yasu Lv;
Yasu Lv
†Department of Cell Biology and Medical Genetics, Research Center for Molecular Medicine, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310000, China
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Zan Huang;
Zan Huang
*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
‡Jiangsu Province Key Laboratory of Gastrointestinal Nutrition and Animal Health, Nanjing Agriculture University, Nanjing 210095, China
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Qinghua Wang;
Qinghua Wang
*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
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Anying Song;
Anying Song
*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
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Zhaoyu Lin;
Zhaoyu Lin
*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
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Xiang Gao
Xiang Gao
2
*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
2To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
February 18 2015
Revision Received:
March 25 2015
Accepted:
March 31 2015
Accepted Manuscript online:
March 31 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem J (2015) 468 (2): 325–336.
Article history
Received:
February 18 2015
Revision Received:
March 25 2015
Accepted:
March 31 2015
Accepted Manuscript online:
March 31 2015
Connected Content
A commentary has been published:
GSDM family genes meet autophagy
Citation
Peiliang Shi, An Tang, Li Xian, Siyuan Hou, Dayuan Zou, Yasu Lv, Zan Huang, Qinghua Wang, Anying Song, Zhaoyu Lin, Xiang Gao; Loss of conserved Gsdma3 self-regulation causes autophagy and cell death. Biochem J 1 June 2015; 468 (2): 325–336. doi: https://doi.org/10.1042/BJ20150204
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