Yuan Wen, Cui Cong-Cong, Li Jing, Xu Yan-Hua, Fan Chun-E, Chen Yu-Chen, Fan Hong-Wei, Hu Bing-Xue, Shi Mei-Yun, Sun Zhi-Yuan, Wang Pei, Ma Teng-Xiang, Zhang Zhao, Zhu Min-Sheng, Chen Hua-Qun
The Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210008, China.
iScience. 2022 Nov 8;25(11):105446. doi: 10.1016/j.isci.2022.105446. eCollection 2022 Nov 18.
Transmembrane protein 16A (TMEM16A) localizes at plasma membrane and controls chloride influx in various type of cells. We here showed an intracellular localization pattern of TMEM16A molecules. In myoblasts, TMEM16A was primarily localized to the cytosolic compartment and partially co-localized with intracellular organelles. The global deletion of TMEM16A led to severe skeletal muscle developmental defect. observation showed that the proliferation of -/- myoblasts was significantly promoted along with activated ERK1/2 and Cyclin D expression; the myogenic differentiation was impaired accompanied by the enhanced caspase 12/3 activation, implying enhanced endoplasmic reticulum (ER) stress. Interestingly, the bradykinin-induced Ca release from ER calcium store was significantly enhanced after TMEM16A deletion. This suggested a suppressing role of intracellular TMEM16A in ER calcium release whereby regulating the flux of chloride ion across the ER membrane. Our findings reveal a unique location pattern of TMEM16A in undifferentiated myoblasts and its role in myogenesis.
跨膜蛋白16A（TMEM16A）定位于质膜，控制各种类型细胞中的氯离子内流。我们在此展示了TMEM16A分子的细胞内定位模式。在成肌细胞中，TMEM16A主要定位于胞质区室，并部分与细胞内细胞器共定位。TMEM16A的整体缺失导致严重的骨骼肌发育缺陷。观察表明，-/-成肌细胞的增殖随着ERK1/2和细胞周期蛋白D表达的激活而显著促进；成肌分化受损，同时半胱天冬酶12/3激活增强，这意味着内质网（ER）应激增强。有趣的是，TMEM16A缺失后，缓激肽诱导的内质网钙库钙释放显著增强。这表明细胞内TMEM16A在内质网钙释放中起抑制作用，从而调节氯离子跨内质网膜的通量。我们的研究结果揭示了TMEM16A在未分化成肌细胞中的独特定位模式及其在肌生成中的作用。
