A robust and efficient cellular response to lysosomal membrane damage prevents leakage from the lysosome lumen into the cytoplasm. This response is understood to happen through either lysosomal membrane repair or lysophagy. Here we report exocytosis as a third response mechanism to lysosomal damage, which is further potentiated when membrane repair or lysosomal degradation mechanisms are impaired. We show that Connexin43 (Cx43), a protein canonically associated with gap junctions, is recruited from the plasma membrane to damaged lysosomes, promoting their secretion and accelerating cell recovery. The effects of Cx43 on lysosome exocytosis are mediated by a reorganization of the actin cytoskeleton that increases plasma membrane fluidity and decreases cell stiffness. Furthermore, we demonstrate that Cx43 interacts with the actin nucleator Arp2, the activity of which was shown to be necessary for Cx43-mediated actin rearrangement and lysosomal exocytosis following damage. These results define a novel mechanism of lysosomal quality control whereby Cx43-mediated actin remodelling potentiates the secretion of damaged lysosomes.

中文翻译：

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Connexin43 通过肌动蛋白重塑促进受损溶酶体的胞吐作用。


细胞对溶酶体膜损伤的强大而有效的反应可防止溶酶体腔渗漏到细胞质中。这种反应被理解为通过溶酶体膜修复或溶酶体自噬发生。在这里，我们报道了胞吐作用作为溶酶体损伤的第三种反应机制，当膜修复或溶酶体降解机制受损时，这种反应会进一步增强。我们表明，Connexin43 （Cx43） 是一种与间隙连接经典相关的蛋白质，从质膜募集到受损的溶酶体，促进其分泌并加速细胞恢复。Cx43 对溶酶体胞吐作用的影响是由肌动蛋白细胞骨架的重组介导的，肌动蛋白细胞骨架的重组增加了质膜流动性并降低了细胞刚度。此外，我们证明 Cx43 与肌动蛋白成核剂 Arp2 相互作用，其活性被证明是 Cx43 介导的肌动蛋白重排和损伤后溶酶体胞吐作用所必需的。这些结果定义了溶酶体质量控制的新机制，其中 Cx43 介导的肌动蛋白重塑增强了受损溶酶体的分泌。