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

Abstract

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.

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

“…Towards the end of their lifetime, GPCRs are internalised from the cell surface into the membranes of endosomes [ 21 ]. These can later fuse with lysosomes, where the receptors are eventually degraded [ 22 ]. Beyond this “classical” lifecycle of GPCRs as cell surface receptors, an increasing body of studies finds GPCRs being terminally trafficked to organellar membranes [ 23 , 24 , 25 ].…”

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“…It may be noted that there is abundant evidence for GPCR expression, localization, and function at nuclear [ 89 ], mitochondrial [ 90 , 91 ], or other intracellular membranes, such as melanosomal membranes [ 92 ], in addition to GPCR transport from the endoplasmic reticulum (ER) to the Golgi apparatus, transport vesicles, PM, and then from the PM by endocytosis to endosomes/lysosomes [ 61 , 93 , 94 ]. Cardiomyocytes, for example, are endowed with multiple nuclear-membrane GPCR of the A class, such as α1-, β1-, β3-adrenergic receptors, and AT1R and AT2R angiotensin receptors [ 95 , 96 , 97 ].…”

Toxoplasma gondii RPL40 is a circulating antigen with immune protection effect

“…The isopeptide linkages between the glycine (G) 76 and lysine (K) 48 or K29 of ubiquitin initiates enzyme-dependent degradation of ubiquitin binding proteins (Pickart 2000(Pickart , 2001. Second, recent studies also indicate that ubiquitin plays an essential role in intracellular signal transduction (Su et al 2013, Dores andTrejo 2019). Other biological processes include the regulation of ribosomal function (Spence et al 2000), transcription (Bhat and Greer 2011), mitochondrial DNA inheritance (Lee et al 2010) and DNA repair (Hedglin and Benkovic 2015).…”