Interplay of Endosomal pH and Ligand Occupancy in Integrin α5β1 Ubiquitination, Endocytic Sorting, and Cell Migration
Interplay of Endosomal pH and Ligand Occupancy in Integrin α5β1 Ubiquitination, Endocytic Sorting, and Cell Migration
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DOI：
10.1016/j.celrep.2015.09.024
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发表时间：
2015-10-20
期刊：
影响因子：
8.8
通讯作者：
Pause, Arnim
中科院分区：
文献类型：
--
作者：
Kharitidi, Dmitri;Apaja, Pirjo M.;Pause, Arnim
整合素的膜运输在细胞增殖和迁移中起关键作用。内吞整合素如何靶向回收或溶酶体递送还不完全清楚。在这里，我们表明，纤连蛋白（FN）结合α 5 β 1整合素触发受体复合物的泛素化和内化。酸化促进FN在体外和早期内体中从整合素α 5 β 1解离，促进受体复合物通过USP 9 x去泛素化并再循环至细胞表面。根据受体的残余配体占有率，一些α 5 β 1整联蛋白保持泛素化并被ESCRTO/I捕获，含有含组氨酸结构域的蛋白酪氨酸磷酸酶（HD-PTP）和泛素相关蛋白1（UBAP 1），并被定向用于溶酶体蛋白水解，限制受体下游信号传导和细胞迁移。因此，HD-PTP或UBAP 1缺失赋予促侵袭表型。因此，受体再敏感化和细胞迁移需要pH依赖性FN-整合素解离和活化整合素α 5 β 1的去遍在蛋白化，这代表了调节肿瘤侵袭力的潜在靶点。
Membrane trafficking of integrins plays a pivotal role in cell proliferation and migration. How endocytosed integrins are targeted either for recycling or lysosomal delivery is not fully understood. Here, we show that fibronectin (FN) binding to alpha 5 beta 1 integrin triggers ubiquitination and internalization of the receptor complex. Acidification facilitates FN dissociation from integrin alpha 5 beta 1 in vitro and in early endosomes, promoting receptor complex deubiquitination by the USP9x and recycling to the cell surface. Depending on residual ligand occupancy of receptors, some alpha 5 beta 1 integrins remain ubiquitinated and are captured by ESCRTO/I, containing histidine domain-containing protein tyrosine phosphatase (HD-PTP) and ubiquitin-associated protein 1 (UBAP1), and are directed for lysosomal proteolysis, limiting receptor downstream signaling and cell migration. Thus, HD-PTP or UBAP1 depletion confers a pro-invasive phenotype. Thus, pH-dependent FN-integrin dissociation and deubiquitination of the activated integrin alpha 5 beta 1 are required for receptor resensitization and cell migration, representing potential targets to modulate tumor invasiveness.