Department of Biology, Hofstra University, Hempstead, New York.
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California.
Traffic. 2019 Feb;20(2):101-109. doi: 10.1111/tra.12619. Epub 2018 Nov 18.
Ubiquitin is covalently attached to substrate proteins in the form of a single ubiquitin moiety or polyubiquitin chains and has been generally linked to protein degradation, however, distinct types of ubiquitin linkages are also used to control other critical cellular processes like cell signaling. Over forty mammalian G protein-coupled receptors (GPCRs) have been reported to be ubiquitinated, but despite the diverse and rich complexity of GPCR signaling, ubiquitin has been largely ascribed to receptor degradation. Indeed, GPCR ubiquitination targets the receptors for degradation by lysosome, which is mediated by the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery, and the proteasome. This has led to the view that ubiquitin and ESCRTs primarily function as the signal to target GPCRs for destruction. Contrary to this conventional view, studies indicate that ubiquitination of certain GPCRs and canonical ubiquitin-binding ESCRTs are not required for receptor degradation and revealed that diverse and complex pathways exist to regulate endo-lysosomal sorting of GPCRs. In other studies, GPCR ubiquitination has been shown to drive signaling and not receptor degradation and further revealed novel insight into the mechanisms by which GPCRs trigger the activity of the ubiquitination machinery. Here, we discuss the diverse pathways by which ubiquitin controls GPCR endo-lysosomal sorting and beyond.
泛素以单泛素部分或多泛素链的形式共价连接到底物蛋白上，通常与蛋白质降解有关，然而，不同类型的泛素连接也被用于控制其他关键的细胞过程，如细胞信号转导。已经报道了超过四十种哺乳动物 G 蛋白偶联受体 (GPCR) 被泛素化，但是尽管 GPCR 信号具有多样和丰富的复杂性，泛素主要被归因于受体降解。事实上，GPCR 泛素化将受体靶向溶酶体进行降解，这是由内体分选复合物必需的运输 (ESCRT) 机制和蛋白酶体介导的。这导致了这样一种观点，即泛素和 ESCRTs 主要作为信号将 GPCR 靶向破坏。与这种传统观点相反，研究表明，某些 GPCR 的泛素化和规范的泛素结合 ESCRTs 不是受体降解所必需的，并揭示了存在多种复杂的途径来调节 GPCR 的内体 - 溶酶体分拣。在其他研究中，已经表明 GPCR 泛素化可以驱动信号转导而不是受体降解，并进一步揭示了 GPCR 触发泛素化机制活性的机制的新见解。在这里，我们讨论了泛素控制 GPCR 内体 - 溶酶体分拣的多种途径及其它方面。
