Ubiquitination of α5β1 lntegrin Controls Fibroblast Migration through Lysosomal Degradation of Fibronectin-lntegrin Complexes
Ubiquitination of α5β1 lntegrin Controls Fibroblast Migration through Lysosomal Degradation of Fibronectin-lntegrin Complexes
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DOI：
10.1016/j.devcel.2010.06.010
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发表时间：
2010-07-20
影响因子：
11.8
通讯作者：
Stenmark, Harald
中科院分区：
文献类型：
--
作者：
Lobert, Viola Helene;Brech, Andreas;Stenmark, Harald
细胞迁移需要整合素的内吞和循环，但目前尚不清楚是否参与了这些膜蛋白的降解。在这里，我们证明了在迁移细胞中，内吞的纤维连接蛋白受体的一部分，α5β1整合素，与纤维连接蛋白一起被分选成多囊内体，并在溶酶体中降解。这种分选需要纤维连接蛋白诱导的α5亚基的泛素化，以及与α5β1整合素相互作用的运输所需的内体分选复合体(ESCRT)机械的活性。重要的是，我们证明了α5泛素化和ESCRT功能都是成纤维细胞正常迁移所必需的。我们认为，需要通过ESCRT途径通过配体介导的α5β1整合素的降解，以防止配体结合的整合素在内体积累，否则可能形成非生产性黏附位点。因此，纤维连接蛋白和α5β1整合素以类似于生长因子及其受体的方式被运输到溶酶体。
Cell migration requires endocytosis and recycling of integrins, but it is not known whether degradation of these membrane proteins is involved. Here we demonstrate that in migrating cells, a fraction of the endocytosed fibronectin receptor, alpha 5 beta 1 integrin, is sorted into multivesicular endosomes together with fibronectin and degraded in lysosomes. This sorting requires fibronectin-induced ubiquitination of the alpha 5 subunit, and the activity of the endosomal sorting complex required for transport (ESCRT) machinery, which interacts with alpha 5 beta 1 integrin. Importantly, we demonstrate that both alpha 5 ubiquitination and ESCRT functions are required for proper migration of fibroblasts. We propose that ligand-mediated degradation of alpha 5 beta 1 integrin via the ESCRT pathway is required in order to prevent endosomal accumulation of ligand-bound integrins that might otherwise form nonproductive adhesion sites. Fibronectin and alpha 5 beta 1 integrin therefore are trafficked to lysosomes in a similar way to growth factors and their receptors.