Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1.

ABSTRACT: 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 le

SUBMITTER: Mao H 

PROVIDER: S-EPMC6776484 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature