Figure 1.

Role of ubiquitin in GPCR trafficking. (1) Many GPCRs have been described to undergo agonist-induced ubiquitination and down-regulation. Upon endocytosis, they are often directed for lysosomal degradation via the conserved endosomal-sorting complex required for the transport (ESCRT) machinery (1a); however, some of them can be deubiquitinated and directed to the resensitization pathway (1b). (2) Constitutive ubiquitination of frizzled-4 receptor (FZD₄R) promotes its internalization and lysosomal degradation, while deubiquitination leads to its recycling and increased cell surface expression. (3) Some GPCRs are basally ubiquitinated (steady-state) and upon agonist binding are deubiquitinated and internalized. After subsequent ubiquitination, they can recycle back to the cell surface. (4) Some properly folded GPCRs (e.g., A_2AR) require deubiquitination to be delivered to the cell surface. (5) Ubiquitination also functions as a quality control system in which misfolded, polyubiquitinated receptors are directed for proteasomal degradation via the endoplasmic reticulum-associated degradation (ERAD) pathway. (6) Some GPCRs are ubiquitinated at the plasma membrane and are directed to the proteasome via a poorly understood process.