The primary cilium is a microtubule-based sensory organelle.The molecular mechanism that regulates ciliary dynamics remains elusive.Here,we report an unexpected finding that MLN4924,a small molecule inhibitor of NEDD8-activating enzyme (NAE),blocks primary ciliary formation by inhibiting synthesis/assembly and promoting disassembly.This is mainly mediated by MLN4924-induced phosphorylation of AKT1 at Ser473 under serum-starved,ciliary-promoting conditions.Indeed,pharmaceutical inhibition (by MK2206) or genetic depletion (via siRNA) of AKT1 rescues MLN4924 effect,indicating its causal role.Interestingly,pAKT1-Ser473 activity regulates both ciliary synthesis/assembly and disassembly in a MLN4924 dependent manner,whereas pAKT-Thr308 determines the ciliary length in MLN4924-independent but VHL-dependent manner.Finally,MLN4924 inhibits mouse hair regrowth,a process requires ciliogenesis.Collectively,our study demonstrates an unexpected role of a neddylation inhibitor in regulation of ciliogenesis via AKT1,and provides a proof-of-concept for potential utility of MLN4924 in the treatment of human diseases associated with abnormal ciliogenesis.