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Molecular basis of oligoubiquitin-dependent internalization of membrane proteins in mammalian cells

机译：寡泛素依赖性内膜蛋白在哺乳动物细胞中内化的分子基础

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Ubiquitination induced down-regulation of cell surface proteins by internalization and lysosomal targeting plays a fundamental role in cell physiology and pathogenesis of diseases. The molecular basis of a single ubiquitin (Ub) as an autonomous endocytic signal, the widely accepted mechanism, however, remains elusive in higher eukaryotes. Using Ub containing reporter proteins without signalling abilities, we present evidence that only multiple Ub moieties, linked either covalently or assembled as oligomers with an intact interface for recognition by Ub-interacting motifs (UIMs), are recognized by the endocytic machinery in vivo and associate with a subset of Ub-binding clathrin adaptors in vitro. Genetic and pharmacological approaches show that internalization of plasma membrane proteins harbouring multiple Ub moieties is clathrin-dependent, but caveolin-independent. Functional assays demonstrate the cargo-dependent involvement of eps15/15R and epsin, UIM containing clathrin adaptors, in the endocytosis of model proteins, CD4 and the activated beta(2)-adrenergic receptor complex, containing polymeric or oligomeric Ub. These results provide a paradigm for the clathrin-mediated uptake of ubiquitinated membrane proteins in mammalian cells, requiring the assembly of multiple UIM-Ub interactions to overcome the low affinity binding of mono-Ub to UIM.
机译：泛素化通过内在化和溶酶体靶向诱导细胞表面蛋白的下调在细胞生理学和疾病发病机理中起着基本作用。单个泛素（Ub）作为自主内吞信号的分子基础是广泛接受的机制，但是，在高等真核生物中仍然难以捉摸。使用没有信号传导能力的含Ub的报告蛋白，我们提供的证据表明，只有内在的Ub部分（共价连接或组装成具有完整界面的寡聚物，可被Ub相互作用的基序（UIMs）识别）在体内被胞吞机制识别并结合在体外具有Ub结合网格蛋白衔接子的子集。遗传和药理学方法表明，具有多个Ub部分的质膜蛋白的内在化与网格蛋白有关，但与小窝蛋白无关。功能分析表明，货物依赖的eps15 / 15R和epsin，UIM包含网格蛋白适配器，参与模型蛋白，CD4和活化的beta（2）-肾上腺素受体复合物的内吞作用，其中包含聚合物或寡聚Ub。这些结果为网格蛋白介导的哺乳动物细胞中泛素化膜蛋白的吸收提供了范例，需要组装多个UIM-Ub相互作用才能克服mono-Ub与UIM的低亲和力结合。

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