Redox-dependent internalization of the purinergic P2Y6 receptor limits colitis progression

After ligand stimulation, many G protein-coupled receptors (GPCRs) undergo beta-arrestin-dependent desensitization, during which they are internalized and either degraded or recycled to the plasma membrane. Some GPCRs are not subject to this type of desensitization because they lack the residues required to interact with beta-arrestins. We identified a mechanism of redox-dependent alternative internalization (REDAI) that promotes the internalization and degradation of the purinergic P2Y(6) receptor (P2Y(6)R). Synthetic and natural compounds containing electrophilic isothiocyanate groups covalently modified P2Y(6)R at Cys(220), which promoted the ubiquitylation of Lys(137) and receptor internalization and degradation in various mouse and human cultured cell lines. Endogenous electrophiles also promoted ligand-dependent P2Y(6)R internalization and degradation. P2Y(6)R is highly abundant in inflammatory cells and promotes the pathogenesis of colitis. Deficiency in P2Y(6)R protected mice against experimentally induced colitis, and mice expressing a form of P2Y(6)R in which Cys(220) was mutated to nonmodifiable serine were more sensitive to the induction of colitis. Several other GPCRs, including A(2B)AR, contain cysteine and lysine residues at the appropriate positions to mediate REDAI, and isothiocyanate stimulated the internalization of A(2B)AR and of a form of P2Y(2)R with insertions of the appropriate residues. Thus, endogenous and exogenous electrophiles may limit colitis progression through cysteine modification of P2Y(6)R and may also mediate internalization of other GPCRs.

Automated summary

This study identified a mechanism called redox-dependent alternative internalization (REDAI) that promotes the internalization and degradation of the purinergic P2Y(6) receptor (P2Y(6)R). The researchers found that both synthetic and natural compounds containing electrophilic isothiocyanate groups can modify P2Y(6)R and facilitate its internalization and degradation. This mechanism, mediated by cysteine modification, may also play a role in the internalization of other G protein-coupled receptors (GPCRs) and potentially limit the progression of colitis.