美国加州大学旧金山分校詹裕农研究组发现，果蝇TMEM63和小鼠TMEM63A是溶酶体机械感知的离子通道。相关论文于2024年2月22日在线发表在《自然—细胞生物学》杂志上。

研究人员发现果蝇的TMEM63（DmTMEM63）离子通道是溶酶体这一主要降解细胞器的内在机械传感器。内源性DmTMEM63蛋白定位于溶酶体，介导溶酶体的机械敏感性并调节溶酶体的形态和功能。Tmem63突变体果蝇表现出溶酶体降解受损、突触丧失、进行性运动障碍和早期死亡，其中一些突变体表型再现了TMEM63相关人类疾病的症状。

重要的是，小鼠TMEM63A在Neuro-2a细胞中介导溶酶体机械敏感性，这表明其在哺乳动物中的功能保持不变。这些发现揭示了DmTMEM63通道在溶酶体中的功能及其在体内的生理作用，并为探索亚细胞器的机械敏感过程提供了分子基础。

据介绍，细胞能感知物理力并将其转化为电子或化学信号，这一过程被称为机械传导。大量研究集中于质膜的机械传导，而对于细胞内细胞器是否和如何感知机械力以及细胞器机械传感的生理功能却知之甚少。

附：英文原文

Title: Drosophila TMEM63 and mouse TMEM63A are lysosomal mechanosensory ion channels

Author: Li, Kai, Guo, Yanmeng, Wang, Yayu, Zhu, Ruijun, Chen, Wei, Cheng, Tong, Zhang, Xiaofan, Jia, Yinjun, Liu, Ting, Zhang, Wei, Jan, Lily Yeh, Jan, Yuh Nung

Issue&Volume: 2024-02-22

Abstract: Cells sense physical forces and convert them into electrical or chemical signals, a process known as mechanotransduction. Whereas extensive studies focus on mechanotransduction at the plasma membrane, little is known about whether and how intracellular organelles sense mechanical force and the physiological functions of organellar mechanosensing. Here we identify the Drosophila TMEM63 (DmTMEM63) ion channel as an intrinsic mechanosensor of the lysosome, a major degradative organelle. Endogenous DmTMEM63 proteins localize to lysosomes, mediate lysosomal mechanosensitivity and modulate lysosomal morphology and function. Tmem63 mutant flies exhibit impaired lysosomal degradation, synaptic loss, progressive motor deficits and early death, with some of these mutant phenotypes recapitulating symptoms of TMEM63-associated human diseases. Importantly, mouse TMEM63A mediates lysosomal mechanosensitivity in Neuro-2a cells, indicative of functional conservation in mammals. Our findings reveal DmTMEM63 channel function in lysosomes and its physiological roles in vivo and provide a molecular basis to explore the mechanosensitive process in subcellular organelles.

DOI: 10.1038/s41556-024-01353-7

Source: https://www.nature.com/articles/s41556-024-01353-7