TMEM63B channel is the mechanosensor in alveolar epithelial type II cells

Shi-Yu Zhan; Xiao-Yu Teng; Dan Wu; Yunfeng Zhu; Tian-Zi Zhang; Hong-Li Guo; Xiaofeng Tan; Guolin Yang; Gui-Zhou Li; Yue-Ying Wang; Bi-Xian Zhong; Gui-Fang Duan; Feng Chen; Jie Xu; Yun Stone Shi

doi:10.1016/j.jgg.2026.04.016

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TMEM63B channel is the mechanosensor in alveolar epithelial type II cells

doi: 10.1016/j.jgg.2026.04.016

a. Department of Neurology, Nanjing Drum Tower Hospital, Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School, Nanjing University, Nanjing, Jiangsu 210032, China;
b. Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, Guangdong 519031, China;
c. Institute of Precision Medicine, First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, Guangdong 510062, China;
d. Pharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, China;
e. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

Funds:

We would like to thank Chi-Chung Hui at the University of Toronto for his insights into the manuscript. This work was supported by grants from the National Natural Science Foundation of China (32330044 to Y.S.S., 82572130 and 82201615 to X.-Y.T., and 82101393 to D.W.).

Received Date: 2026-03-09
Accepted Date: 2026-04-23
Rev Recd Date: 2026-04-19

Available Online: 2026-04-30

Abstract

Abstract

Inspiration-induced mechanical stretching serves as the primary driving force for pulmonary surfactant secretion from alveolar epithelial type II (AT2) cells. However, the mechanism by which AT2 cells sense mechanical stimuli remains elusive. Here, we demonstrate that TMEM63B functions as a critical mechanosensor on the plasma membrane of AT2 cells. We find that stretch induces significant currents in AT2 cells. Using Tmem63b^HA-fl/HA-fl mice, we show that TMEM63B is expressed on the plasma membrane of AT2 cells. Deletion of TMEM63B in AT2 cells abolishes the stretch-induced currents and suppresses the secretion of pulmonary surfactant. Activation of TMEM63B causes Ca²⁺ influx, lamellar body (LB) fusion, and pulmonary surfactant secretion. These processes are markedly impaired upon TMEM63B deletion. In contrast, ATP-induced Ca²⁺ influx and LB fusion are unaffected by TMEM63B deletion, indicating that TMEM63B plays a specialized role in sensing mechanical stretch in the lungs. Therefore, our study establishes TMEM63B as a key mechanosensor critical for AT2 cell-mediated pulmonary surfactant secretion.
- TMEM63B,
- Mechanosensor,
- Alveolar epithelial type II cells,
- Pulmonary surfactant secretion,
- Ca²⁺ entry

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References(58)

References

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