Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1.

Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1.
Protein Cell. 2019 Mar 09;:
Authors: Mao H, Tang Z, Li H, Sun B, Tan M, Fan S, Zhu Y, Sun Y
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 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.
PMID: 30850948 [PubMed - as supplied by publisher]

Source: Protein and Cell - March 10, 2019 Category: Cytology Tags: Protein Cell Source Type: research