Cell cycle-dependent ubiquitylation and destruction of NDE1 by CDK5-FBW7 regulates ciliary length

Primary cilia start forming within the G1 phase of the cell cycle and continue to grow as cells exit the cell cycle (G0). They start resorbing when cells re‐enter the cell cycle (S phase) and are practically invisible in mitosis. The mechanisms by which cilium biogenesis and disassembly are coupled to the cell cycle are complex and not well understood. We previously identified the centrosomal phosphoprotein NDE1 as a negative regulator of ciliary length and showed that its levels inversely correlate with ciliogenesis. Here, we identify the tumor suppressor FBW7 (also known as FBXW7, CDC4, AGO, or SEL‐10) as the E3 ligase that mediates the destruction of NDE1 upon entry into G1. CDK5, a kinase active in G1/G0, primes NDE1 for FBW7‐mediated recognition. Cells depleted of FBW7 or CDK5 show enhanced levels of NDE1 and a reduction in ciliary length, which is corrected in cells depleted of both FBW7 or CDK5 and NDE1. These data show that cell cycle‐dependent mechanisms can control ciliary length through a CDK5‐FBW7‐NDE1 pathway. Synopsis Biogenesis and disassembly of primary cilia are coupled to the cell cycle by incompletely understood mechanisms. This study identifies such a link, by which a quiescence‐specific kinase controls the levels of a negative regulator of ciliary length. Primary cilia are formed in quiescent cells. NDE1, a negative regulator of ciliary length, is downregulated in quiescent cells. CDK5, a kinase active in quiescent cells, phosphorylates NDE1 within an FBW7‐specific phosphodegron. The FBW7 E3 ligase recognizes and targets phosphorylated NDE1 for degradation via the ubiquitin–proteasome system. Destruction of NDE1 in G1/G0 allows cilia to reach their proper length. Graphical Abstract Quiescence‐specific kinase CDK5 initiates NDE1 degradation to couple cell cycle state to length control of primary cilia.