Bidirectional regulation of structural damage on autophagy in the C. elegans epidermis
Bidirectional regulation of structural damage on autophagy in the C. elegans epidermis
复制标题
线虫表皮结构损伤对自噬的双向调节
DOI：
10.1080/15548627.2022.2047345
复制
发表时间：
2022-03-18
期刊：
影响因子：
13.3
通讯作者：
Zhang, Huimin
中科院分区：
文献类型：
--
作者：
Fu, Rong;Jiang, Xiaowan;Zhang, Huimin
饥饿、细胞器损伤、热应激、缺氧和病原体感染等多种干扰都能影响自噬过程。然而，大自噬/自噬机制如何通过细胞的结构损伤内在地调节仍然在很大程度上未知。在这项工作中，我们利用C。elegans表皮作为模型来解决这个问题。我们的研究结果表明，机械损伤造成的结构损伤对同一表皮细胞内的自噬具有近端抑制作用和远端促进作用。通过破坏单个机械支持结构，我们发现只有基底细胞外基质或底层肌肉细胞的损伤才能激活表皮中明显的自噬反应。相反，表皮细胞在顶端侧的结构破坏抑制了由不同应激因素引起的自噬激活。机制研究表明，结构损伤对表皮自噬的基础促进作用是通过基底半桥粒受体和LET-363/MTOR介导的机械转导途径介导的，而顶端抑制作用主要是通过激活钙信号来进行的。表皮中升高的自噬对细胞存活对抗结构损伤起着有害而非有益的作用。从这些研究中获得的结果不仅有助于我们更好地了解结构损伤和自噬相关疾病的发病机制，而且还可以通过跨物种细胞的结构和机械特性来深入了解自噬调节的更一般规则。
A variety of disturbances such as starvation, organelle damage, heat stress, hypoxia and pathogen infection can influence the autophagic process. However, how the macroautophagy/autophagy machinery is regulated intrinsically by structural damage of the cell remains largely unknown. In this work, we utilized the C. elegans epidermis as the model to address this question. Our results showed that structural damage by mechanical wounding exerted proximal inhibitory effect and distant promotional effect on autophagy within the same epidermal cell. By disrupting individual mechanical supporting structures, we found that only damage of the basal extracellular matrix or the underlying muscle cells activated a distinct autophagic response in the epidermis. On the contrary, structural disruption of the epidermal cells at the apical side inhibited autophagy activation caused by different stress factors. Mechanistic studies showed that the basal promotional effect of structural damage on epidermal autophagy was mediated by a mechanotransduction pathway going through the basal hemidesmosome receptor and LET-363/MTOR, while the apical inhibitory effect was mostly carried out by activation of calcium signaling. Elevated autophagy in the epidermis played a detrimental rather than a beneficial role on cell survival against structural damage. The results obtained from these studies will not only help us better understand the pathogenesis of structural damage- and autophagy-related diseases, but also provide insight into more generic rules of autophagy regulation by the structural and mechanical properties of cells across species.