title: Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension.
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.
authors.affiliation: 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.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Kasahara
authors.affiliation: Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kawakami
authors.affiliation: Virology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.affiliation: Electron Microscope Laboratory, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Yonemura
authors.affiliation: Japan Biological Informatics Consortium (JBiC), Tokyo 135-8073, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kawamura
authors.affiliation: Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan.
authors.forename: Saho
authors.initials: S
authors.lastname: Era
authors.affiliation: Laboratory of Cell Asymmetry, RIKEN Center of Developmental Biology, Kobe 650-0047, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Matsuzaki
authors.affiliation: Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Goshima
authors.affiliation: 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.
authors.forename: Masaki
authors.initials: M
authors.lastname: Inagaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D054468:Axoneme / Q000201:enzymology* / Q000378:metabolism*; D002502:Centrioles / Q000201:enzymology / Q000378:metabolism*; D002923:Cilia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C503645:CUL3 protein, human; D044842:Cullin Proteins; C000600308:KCTD17 protein, human; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex