Cilia act as signalling hubs by converting extracellular signals into intracellular responses. The links between cilia and the sonic hedgehog (SHH) pathway are intensely studied, as the disruption of SHH signalling is the underlying cause of many cilia-related disorders. In a new study, Pfirrmann and colleagues (Hantel et al., 2022) investigate whether the GID/CTLH protein complex (GID complex), a multi-subunit E3 ubiquitin ligase, is involved in cilia-dependent SHH signalling. They first show, in both a fibroblast cell line and Xenopus laevis embryos, that subunits of the GID complex localise to the basal body and the axoneme of primary as well as motile mono-cilia. The authors then demonstrate that knocking out RMND5A, a subunit of the complex, leads to perturbed activation of SHH signalling following the addition of a pathway agonist. Moreover, RMND5A deficiency results in reduced concentrations of several SHH proteins at the cilium, suggesting that the impairment of protein transport or import may underlie the observed signalling defects. Finally, in Xenopus embryos, knockdown of rmnd5a using morpholinos leads to various ciliopathy-like phenotypes and affects the proper formation of the forebrain, implicating a role for the GID complex in SHH patterning. Taken together, these findings highlight a function of the GID complex in regulating protein homeostasis of SHH components at primary cilia and will guide future work to understand the molecular basis of ciliopathies.
