RABL2 positively controls localization of GPCRs in mammalian primary cilia

Abstract

Primary cilium, a solitary protrusion from most mammalian cells, functions as a cell's sensor by receiving extra-cellular signals through receptors and channels accumulated in the organelle. Certain G-protein coupled receptors (GPCRs) specifically localize to membrane compartment of the primary cilia. To gain insight into the mechanisms that regulate ciliary GPCR sorting, we investigated an atypical small GTPase RAB-like 2 (RABL2). RABL2 recruitment to the mother centriole is dependent on distal appendage proteins, CEP164 and CEP83. We found that silencing of RABL2 causes mis-targeting of ciliary GPCRs, GPR161 and HTR6, whereas overexpression of RABL2 resulted in accumulation of these receptors in the organelle. Ablation of CEP19 and IFT-B, which interact with RABL2, also lead to mis-localization of GPR161. RABL2 controls localization of GPR161 independently of TULP3, which promotes entry of ciliary GPCRs. We further demonstrated that RABL2 physically associates with ciliary GPCRs. Altogether, these studies suggest that RABL2 plays an important role in trafficking of ciliary GPCRs at the ciliary base in mammalian cells.