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CRF binding protein facilitates the presence of CRF type 2α receptor on the cell surface

Significance Corticotropin releasing factor binding protein (CRF-BP) belongs to the CRF family that is fundamental in the stress response and in the interaction between stress and addiction. The mechanisms by which CRF-BP regulates the CRF system are not fully understood. Most G protein-coupled receptors (GPCRs) are located mainly intracellularly and depend on specific escort proteins for their trafficking to the cell surface. CRF2αR is also located intracellularly; however, no escort protein regulating its presence on the cell surface has been described. We show that CRF-BP interacts with CRF2αR, acting as an escort protein, increasing the presence of the receptor on the cell surface. Corticotropin releasing factor binding protein (CRF-BP) was originally recognized as CRF sequestering protein. However, its differential subcellular localization in different brain nuclei suggests that CRF-BP may have additional functions. There is evidence that CRF-BP potentiates CRF and urocortin 1 actions through CRF type 2 receptors (CRF2R). CRF2R is a G protein-coupled receptor (GPCR) that is found mainly intracellularly as most GPCRs. The access of GPCRs to the cell surface is tightly regulated by escort proteins. We hypothesized that CRF-BP binds to CRF2R, exerting an escort protein role. We analyzed the colocalization of CRF-BP and CRF2R in cultured rat mesencephalic neurons, and the localization and interaction of heterologous expressed CRF-BP and CRF2αR in yeast, human embryonic kidney 293, and rat pheochromocytoma 12 cells. Our results showed that CRF-BP and CRF2R naturally colocalize in the neurites of cultured mesencephalic neurons. Heterologous expression of each protein showed that CRF-BP was localized mainly in secretory granules and CRF2αR in the endoplasmic reticulum. In contrast, CRF-BP and CRF2αR colocalized when both proteins are coexpressed. Here we show that CRF-BP physically interacts with the CRF2αR but not the CRF2βR isoform, increasing CRF2αR on the cell surface. Thus, CRF-BP emerges as a GPCR escort protein increasing the understanding of GPCR trafficking.