Shi Peiliang, Tang An, Xian Li, Hou Siyuan, Zou Dayuan, Lv Yasu, Huang Zan, Wang Qinghua, Song Anying, Lin Zhaoyu, Gao Xiang
*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.
†Department of Cell Biology and Medical Genetics, Research Center for Molecular Medicine, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310000, China.
Biochem J. 2015 Jun 1;468(2):325-36. doi: 10.1042/BJ20150204.
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.
Gasdermin A3（Gsdma3）最初是在与小鼠突变体脱发表型相关的研究中被鉴定出来的。我们之前的研究发现，AE突变小鼠的Gsdma3 C末端结构域存在Y344H替换，表现出炎症依赖性脱发和皮肤破损[Zhou等人（2012年），《美国病理学杂志》180卷，763 - 774页]。有趣的是，我们发现新产生的Gsdma3基因敲除突变小鼠并未表现出皮肤形态异常，这表明在正常生理条件下，Gsdma3对于表皮细胞分化和毛发周期维持并非必需。同样，转染野生型（WT）Gsdma3的人胚肾（HEK）293细胞和HaCaT细胞未显示出异常形态。然而，Gsdma3 Y344H突变诱导了自噬。Gsdma3的N末端结构域而非C末端结构域也表现出类似的促自噬活性。Gsdma3 Y344H突变蛋白和N末端结构域诱导的自噬与线粒体及活性氧生成有关。C末端结构域的共表达逆转了N末端结构域诱导的细胞自噬。此外，C末端结构域可与N末端结构域共同沉淀。这些数据表明，WT Gsdma3蛋白潜在的促自噬活性通过分子内抑制机制被抑制。对GSDM家族其他成员的研究表明，这种机制在几个亚家族中是保守的。
