Plasma Membrane Repair Is Regulated Extracellularly by Proteases Released from Lysosomes.
Plasma Membrane Repair Is Regulated Extracellularly by Proteases Released from Lysosomes.
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DOI：
10.1371/journal.pone.0152583
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Andrews NW
中科院分区：
文献类型：
--
作者：
Castro-Gomes T;Corrotte M;Tam C;Andrews NW
真核细胞迅速修复其质膜上的伤口。再密封是Ca2+依赖性的，涉及溶酶体的胞吐作用，随后是大量的内吞作用。溶酶体酶酸性鞘磷脂酶的细胞外活性先前显示促进内吞作用和伤口去除。然而，细胞损伤过程中释放的溶酶体蛋白酶是否参与再密封尚不清楚。在这里，我们表明，溶酶体蛋白酶调节质膜修复。细胞外蛋白水解在细胞损伤后不久被检测到，并且该过程的抑制阻断修复。相反，表面蛋白降解促进质膜重新密封。丰富的溶酶体半胱氨酸蛋白酶组织蛋白酶B和L，已知可蛋白水解重塑细胞外基质，在细胞损伤时迅速释放，并且是有效质膜修复所需的。相比之下，抑制乙酰胆碱酯酶或RNAi介导的溶酶体乙酰胆碱酯酶组织蛋白酶D的沉默增强了重新密封，这是一种与细胞表面上活性酸性鞘磷脂酶积累相关的效应。因此，分泌的溶酶体半胱氨酸蛋白酶可通过促进溶酶体酸性鞘磷脂酶的膜进入来促进修复，所述溶酶体酸性鞘磷脂酶促进伤口去除并且随后通过涉及组织蛋白酶D的过程在细胞外下调。
Eukaryotic cells rapidly repair wounds on their plasma membrane. Resealing is Ca2+-dependent, and involves exocytosis of lysosomes followed by massive endocytosis. Extracellular activity of the lysosomal enzyme acid sphingomyelinase was previously shown to promote endocytosis and wound removal. However, whether lysosomal proteases released during cell injury participate in resealing is unknown. Here we show that lysosomal proteases regulate plasma membrane repair. Extracellular proteolysis is detected shortly after cell wounding, and inhibition of this process blocks repair. Conversely, surface protein degradation facilitates plasma membrane resealing. The abundant lysosomal cysteine proteases cathepsin B and L, known to proteolytically remodel the extracellular matrix, are rapidly released upon cell injury and are required for efficient plasma membrane repair. In contrast, inhibition of aspartyl proteases or RNAi-mediated silencing of the lysosomal aspartyl protease cathepsin D enhances resealing, an effect associated with the accumulation of active acid sphingomyelinase on the cell surface. Thus, secreted lysosomal cysteine proteases may promote repair by facilitating membrane access of lysosomal acid sphingomyelinase, which promotes wound removal and is subsequently downregulated extracellularly by a process involving cathepsin D.