SNX9 family mediates βarrestin-independent GPCR endocytosis

Agonist-stimulated GPCR endocytosis typically occurs via the multi-faceted adaptor proteins known as βarrestins. However, endocytosis of several GPCRs occurs independently of β-arrestins, suggesting an additional mode of GPCR endocytosis, but the mechanisms remain unknown. Here we provide evidence that sorting nexin 9 (SNX9), a previously described endocytic remodeling protein, functions as a novel cargo adaptor that promotes agonist-stimulated GPCR endocytosis. We show that SNX9 and SNX18, but not β-arrestins, are necessary for endocytosis of the chemokine receptor CXCR4. SNX9 is recruited to CXCR4 at the plasma membrane and interacts directly with the carboxyl-terminal tail of the receptor in a phosphorylation-dependent manner. We also provide evidence that some receptors do not require SNX9 and SNX18 nor β-arrestins for endocytosis, suggesting additional modes for GPCR endocytosis. These results provide novel insights into the mechanisms regulating GPCR trafficking and broaden our overall understanding of GPCR regulation. Research sheds light on mechanisms governing βarrestin-independent endocytosis of GPCRs.