Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1

The primary cilium is a microtubule-based sensory organelle, but the molecular mechanisms controlling its dynamics remain unclear. In this study, we reveal a surprising discovery: MLN4924, a small molecule inhibitor of the NEDD8-activating enzyme (NAE), disrupts primary cilium formation by both hindering its synthesis/assembly and promoting Pevonedistat its disassembly. This effect is largely driven by MLN4924-induced phosphorylation of AKT1 at Ser473 under serum-starved, cilium-promoting conditions. Notably, inhibiting AKT1 pharmacologically (with MK2206) or genetically (using siRNA) reverses the effects of MLN4924, highlighting AKT1′s pivotal role. Intriguingly, pAKT1-Ser473 activity influences both ciliary synthesis/assembly and disassembly in an MLN4924-dependent manner, while pAKT-Thr308 controls ciliary length in a manner independent of MLN4924 but dependent on VHL. Additionally, MLN4924 impedes mouse hair regrowth, a process dependent on ciliogenesis. Overall, our findings uncover an unexpected role of a neddylation inhibitor in the regulation of ciliogenesis via AKT1 and suggest the potential of MLN4924 as a therapeutic agent for diseases linked to abnormal ciliogenesis.