Identification of primary cilia targeting sequences in HTR6 and SSTR3

Resumen del póster presentado al 6th Symposium on Biomedical Research: Advances and Perspectives in Molecular Endocrinology "In Homage to Gabriella Morreale", celebrado en el Instituto de Investigaciones Biomédicas Alberto Sols (IIBM-CSIC) el 31 de mayo de 2019.Serotonin receptor 6 (Htr6) is a neuronal G protein-coupled receptor (GPCR) involved in multiple aspects of brain pathophysiology. Htr6 localizes to primary cilia, microtubule-based plasma membrane protrusions that act as signaling platforms. Htr6 contains a ciliary targeting sequence (CTS) in its third intracellular loop. This CTS (CTS1) is sufficient to confer cilia localization to non-ciliary proteins such as Htr7, a non-ciliary GPCR, or CD8?, a single pass transmembrane protein. Surprisingly, however, CTS1 is not required for Htr6 itself to localize to cilia, suggesting that Htr6 contains another CTS. Here, we have identified a second CTS (CTS2) in the C-terminal tail of Htr6. Like CTS1, the novel CTS2 is sufficient but not necessary for cilia localization. When both CTS1 and CTS2 are mutated, Htr6 no longer accumulates in cilia. Thus, CTS1 and CTS2 act redundantly and are, in combination, both necessary and sufficient for Htr6 ciliary targeting. Furthermore, we have found that the same pattern applies to another ciliary GPCR, namely, Somatostatin receptor 3 (Sstr3). We are now elucidating the mechanisms of action of these novel CTSs.This work was funded by MINECO/FEDER (SAF2015-66568-R) and Ramón y Cajal (RYC2013-14887) grants from the Spanish Ministry of Economy and Competitiveness to F.R.G.GPeer reviewe