biostudies-literatureHantel FMartin Luther UniversityHMU Health and Medical University Potsdam GmbHDeutsche Forschungsgemeinschaftjcs259209https://www.ebi.ac.uk/biostudies/studies/S-EPMC9264362biostudies-literatureUnknown135(9)Cilia are evolutionarily conserved organelles that orchestrate a variety of signal transduction pathways, such as sonic hedgehog (SHH) signaling, during embryonic development. Our recent studies have shown that loss of GID ubiquitin ligase function results in aberrant AMP-activated protein kinase (AMPK) activation and elongated primary cilia, which suggests a functional connection to cilia. Here, we reveal that the GID complex is an integral part of the cilium required for primary cilia-dependent signal transduction and the maintenance of ciliary protein homeostasis. We show that GID complex subunits localize to cilia in both Xenopus laevis and NIH3T3 cells. Furthermore, we report SHH signaling pathway defects that are independent of AMPK and mechanistic target of rapamycin (MTOR) activatiJournal of cell scienceCilia-localized GID/CTLH ubiquitin ligase complex regulates protein homeostasis of sonic hedgehog signaling components.PMC9264362WA3365/2-1EXC-2189GRK 2155FKZ31/06390939984Liu HWalentek PNeuhaus HHantel FVillavicencio-Lorini PFechtner LPfirrmann TArlt DDing JHollemann TGerhardt CfalseCilia-localized GID/CTLH ubiquitin ligase complex regulates protein homeostasis of sonic hedgehog signaling components.Cilia are evolutionarily conserved organelles that orchestrate a variety of signal transduction pathways, such as sonic hedgehog (SHH) signaling, during embryonic development. Our recent studies have shown that loss of GID ubiquitin ligase function results in aberrant AMP-activated protein kinase (AMPK) activation and elongated primary cilia, which suggests a functional connection to cilia. Here, we reveal that the GID complex is an integral part of the cilium required for primary cilia-dependent signal transduction and the maintenance of ciliary protein homeostasis. We show that GID complex subunits localize to cilia in both Xenopus laevis and NIH3T3 cells. Furthermore, we report SHH signaling pathway defects that are independent of AMPK and mechanistic target of rapamycin (MTOR) activati2022-01-01T00:00:00Z2022 May2026-06-01T02:17:48.686Z2025-04-04T03:19:44.711ZS-EPMC92643623554315510.1242/jcs.259209