EFCAB7 and IQCE Regulate Hedgehog Signaling by Tethering the EVC-EVC2 Complex to the Base of Primary Cilia

The Hedgehog (Hh) pathway depends on primary cilia in vertebrates, but the signaling machinery within cilia remains incompletely defined. We report the identification of a complex between two ciliary proteins, EFCAB7 and IQCE, which positively regulates the Hh pathway. The EFCAB7-IQCE module anchors the EVC-EVC2 complex in a signaling microdomain at the base of cilia. EVC and EVC2 genes are mutated in Ellis van Creveld and Weyers syndromes, characterized by impaired Hh signaling in skeletal, cardiac, and orofacial tissues. EFCAB7 binds to a C-terminal disordered region in EVC2 that is deleted in Weyers patients. EFCAB7 depletion mimics the Weyers cellular phenotype—the mislocalization of EVC-EVC2 within cilia and impaired activation of the transcription factor GLI2. Evolutionary analysis suggests that emergence of these complexes might have been important for adaptation of an ancient organelle, the cilium, for an animal-specific signaling network. [Display omitted] [Display omitted] •EFCAB7 and IQCE are positive regulators of Hedgehog signaling•EFCAB7-IQCE complex tethers the EVC-EVC2 complex to the base of cilia•Depletion of EFCAB7 mimics the cellular phenotype seen in an Hh-related ciliopathy•The evolution of these proteins might have adapted cilia for Hh signaling Pusapati et al. identify a protein complex, EFCAB7-IQCE, required for Hedgehog signaling downstream of Smoothened at primary cilia. These proteins localize a Smoothened-binding complex, EVC-EVC2, to a signaling microdomain at the cilium base. Mutations in EVC2 that disrupt the association between these two complexes lead to human skeletal dysplasia.