The deubiquitinating enzyme USP14 controls ciliogenesis and hedgehog signalling

Primary cilia are hair-like organelles that play crucial roles in vertebrate development, organogenesis, and when dysfunctional result in pleiotropic human genetic disorders called ciliopathies, characterized byoverlapping phenotypes, such as renal and hepatic cysts, skeletal defects, retinal degeneration, and CNS malformations. Primary cilia act as communication hubs to transfer extracellular signals into intracellular responses and are essentialfor Hedgehog (Hh) signal transduction in mammals. Despite the renewed interest in this ancient organelle of growing biomedical importance, the molecular mechanisms that trigger cilia formation, extension and ciliary signal transduction are still not fully understood. Here we provide, for the first time, evidence that the deubiquitinase Usp14, a major regulator of the ubiquitin proteasome system (UPS), controls ciliogenesis, cilia elongation and Hh signal transduction. Moreover, we show that pharmacological inhibition of Usp14 positively affects Hh signal transduction in a model ofautosomal dominant polycystic kidney disease (ADPKD).These findings provide new insight into the spectrum of action ofUPS in cilia biology and may provide novel opportunities for therapeutic intervention in human conditions associated with ciliary dysfunction.