RT Journal Article
SR Electronic
T1 HTR6 and SSTR3 ciliary targeting relies on both IC3 loops and C-terminal tails
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000746
DO 10.26508/lsa.202000746
VO 4
IS 3
A1 Pablo Barbeito
A1 Yuki Tachibana
A1 Raquel Martin-Morales
A1 Paula Moreno
A1 Kirk Mykytyn
A1 Tetsuo Kobayashi
A1 Francesc R Garcia-Gonzalo
YR 2021
UL https://www.life-science-alliance.org/content/4/3/e202000746.abstract
AB G protein-coupled receptors (GPCRs) are the most common pharmacological target in human clinical practice. To perform their functions, many GPCRs must accumulate inside primary cilia, microtubule-based plasma membrane protrusions working as cellular antennae. Nevertheless, the molecular mechanisms underlying GPCR ciliary targeting remain poorly understood. Serotonin receptor 6 (HTR6) and somatostatin receptor 3 (SSTR3) are two brain-enriched ciliary GPCRs involved in cognition and pathologies such as Alzheimer’s disease and cancer. Although the third intracellular loops (IC3) of HTR6 and SSTR3 suffice to target non-ciliary GPCRs to cilia, these IC3s are dispensable for ciliary targeting of HTR6 and SSTR3 themselves, suggesting these GPCRs contain additional ciliary targeting sequences (CTSs). Herein, we discover and characterize novel CTSs in HTR6 and SSTR3 C-terminal tails (CT). These CT-CTSs (CTS2) act redundantly with IC3-CTSs (CTS1), each being sufficient for ciliary targeting. In HTR6, RKQ and LPG motifs are critical for CTS1 and CTS2 function, respectively, whereas in SSTR3 these roles are mostly fulfilled by AP[AS]CQ motifs in IC3 and juxtamembrane residues in CT. Furthermore, we shed light on how these CTSs promote ciliary targeting by modulating binding to ciliary trafficking adapters TULP3 and RABL2.