Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1.
10.1007/s13238-019-0614-3
- Author:
Hongmei MAO
1
;
Zaiming TANG
1
;
Hua LI
2
;
Bo SUN
1
;
Mingjia TAN
2
;
Shaohua FAN
2
;
Yuan ZHU
3
;
Yi SUN
4
Author Information
1. The Cancer Institute of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China.
2. Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
3. Gilbert Family Neurofibromatosis Institute, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC, 20010, USA.
4. The Cancer Institute of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China. yisun@zju.edu.cn.
- Publication Type:Journal Article
- Keywords:
AKT;
Cilia;
MLN4924;
VHL;
neddylation;
siRNA
- From:
Protein & Cell
2019;10(10):726-744
- CountryChina
- Language:English
-
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-Ser activity regulates both ciliary synthesis/assembly and disassembly in a MLN4924 dependent manner, whereas pAKT-Thr 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.
