Endo‐lysosomal sorting of G‐protein‐coupled receptors by ubiquitin: Diverse pathways for G‐protein‐coupled receptor destruction and beyond

• Published in: Traffic (Copenhagen, Denmark) Denmark), 2019-02, Vol.20 (2), p.101-109
• Main Authors: Dores, Michael R., Trejo, JoAnn
• Format: Article
• Language: English
• Subjects: ALIX; Animals; ARRDC3; E3 ligases; Endosomal Sorting Complexes Required for Transport - metabolism; Endosomes - metabolism; ESCRT; exosomes; G protein; G protein-coupled receptors; HRS; Humans; Lysosomes - metabolism; NEDD4; PAR1; Proteasomes; Protein Transport; Proteins; Receptors, G-Protein-Coupled - metabolism; Signal transduction; Ubiquitin; Ubiquitination; β‐Arrestins
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/tra.12619

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. Ubiquitination of GPCRs and endocytic adaptor proteins facilitates GPCR trafficking to lysosomes and. In addition, ubiquitination of GPCRs and GPCR effectors can mediate the activation of specific signaling pathways. GPCR ubiquitination is also critical for targeting some GPCRs for degradation by proteasomes. This review highlights the multiple pathways by which ubiquitin controls GPCR endo‐lysosomal sorting and signaling, which expand the function of ubiquitin in regulating GPCR biology.