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Nat Commun. 2014 Oct 1;5:5081. doi: 10.1038/ncomms6081.

Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension.

Author information

1
1] Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan [2] Department of Oncology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan.
2
Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
3
Virology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
4
Electron Microscope Laboratory, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
5
Japan Biological Informatics Consortium (JBiC), Tokyo 135-8073, Japan.
6
Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan.
7
Laboratory of Cell Asymmetry, RIKEN Center of Developmental Biology, Kobe 650-0047, Japan.
8
1] Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan [2] Department of Cellular Oncology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.

Abstract

Primary cilia are microtubule-based sensory organelles that organize numerous key signals during developments and tissue homeostasis. Ciliary microtubule doublet, named axoneme, is grown directly from the distal end of mother centrioles through a multistep process upon cell cycle exit; however, the instructive signals that initiate these events are poorly understood. Here we show that ubiquitin-proteasome machinery removes trichoplein, a negative regulator of ciliogenesis, from mother centrioles and thereby causes Aurora-A inactivation, leading to ciliogenesis. Ciliogenesis is blocked if centriolar trichoplein is stabilized by treatment with proteasome inhibitors or by expression of non-ubiquitylatable trichoplein mutant (K50/57R). Started from two-stepped global E3 screening, we have identified KCTD17 as a substrate-adaptor for Cul3-RING E3 ligases (CRL3s) that polyubiquitylates trichoplein. Depletion of KCTD17 specifically arrests ciliogenesis at the initial step of axoneme extension through aberrant trichoplein-Aurora-A activity. Thus, CRL3-KCTD17 targets trichoplein to proteolysis to initiate the axoneme extension during ciliogenesis.

PMID:
25270598
PMCID:
PMC4205846
DOI:
10.1038/ncomms6081
[Indexed for MEDLINE]
Free PMC Article

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