Rab8 and TNPO1 function as the ciliary transport adapters for GPCRs

The sensory functions of the primary cilium require the specific enrichment of a variety of transmembrane receptors, including G protein-coupled receptors (GPCRs). However, the molecular and cellular mechanisms governing the ciliary targeting of these receptors remain poorly understood. In our previous work, we identified Rab8 and TNPO1 as potential ciliary transport adapters for a range of ciliary membrane proteins, including PKHD1, RP2, RDH8, ARL13B, and RHO (a GPCR), through the formation of a ternary complex with their respective ciliary targeting sequences (CTSs). In this study, we screened nine cilium-localized GPCRs and identified five that interact with both Rab8 and TNPO1 and require the two adapters for ciliary localization. We found that β2 adrenergic receptor contains two CTSs: one in the third intracellular loop and another in the C-terminal cytosolic tail. Only the C-terminal CTS interacts with Rab8 and TNPO1, and its ciliary localization is dependent on both adapters. Our study suggests that Rab8 and TNPO1 might function as ciliary transport adapters for a significant number of GPCRs.