Epithelia must eliminate apoptotic cells to preserve tissue barriers and prevent inflammation. Several different mechanisms exist for apoptotic clearance, including efferocytosis and apical extrusion. We found that extrusion was the first-line response to apoptosis in cultured monolayers and in zebrafish epidermis. During extrusion, the apoptotic cell elicited active lamellipodial protrusions and assembly of a contractile extrusion ring in its neighbours. Depleting E-cadherin compromised both the contractile ring and extrusion, implying that a cadherin-dependent pathway allows apoptotic cells to engage their neighbours for extrusion. We identify RhoA as the cadherin-dependent signal in the neighbour cells and show that it is activated in response to contractile tension from the apoptotic cell. This mechanical stimulus is conveyed by a Myosin VI-dependent mechanotransduction pathway that is necessary both for extrusion and to preserve the epithelial barrier when apoptosis was stimulated. Earlier studies suggested that release of sphingosine-1-phosphate (S1P) from apoptotic cells might define where RhoA was activated. However, we found that although S1P is necessary for extrusion, its contribution does not require a localized source of S1P in the epithelium. We therefore propose a unified view of how RhoA is stimulated to engage neighbour cells for apoptotic extrusion. Here, tension-sensitive mechanotransduction is the proximate mechanism that activates RhoA specifically in the immediate neighbours of apoptotic cells, but this also must be primed by S1P in the tissue environment. Together, these elements provide a coincidence detection system that confers robustness on the extrusion response.

中文翻译：

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凋亡细胞挤出过程中邻近细胞参与的统一视图。

上皮细胞必须消除凋亡细胞，以保留组织屏障并防止炎症。存在几种不同的凋亡清除机制，包括胞吞作用和根尖挤压。我们发现挤压是培养的单层细胞和斑马鱼表皮中对细胞凋亡的一线反应。在挤压过程中，凋亡细胞在其附近引起活跃的片状脂质体突起和收缩性挤压环的组装。耗尽E-钙粘着蛋白会损害收缩环和挤出，这暗示着钙粘着蛋白依赖性途径允许凋亡细胞与其邻居接合以进行挤出。我们将RhoA识别为邻近细胞中的钙粘蛋白依赖性信号，并表明它被激活以响应来自凋亡细胞的收缩张力。这种机械刺激是通过依赖于肌球蛋白VI的机械转导途径来传递的，当刺激细胞凋亡时，挤压和保留上皮屏障都是必需的。较早的研究表明，从凋亡细胞释放1磷酸鞘氨醇（S1P）可能定义了RhoA的激活位置。但是，我们发现尽管S1P对于挤压是必需的，但其贡献不需要上皮中的S1P局部来源。因此，我们提出了如何刺激RhoA参与邻近细胞进行细胞凋亡挤出的统一观点。在这里，张力敏感的机械转导是激活RhoA的最直接机制，特别是在凋亡细胞的直接邻居中激活RhoA，但这在组织环境中也必须由S1P启动。一起，