Counterregulation of cAMP-directed kinase activities controls ciliogenesis

Monia Porpora, Simona Sauchella, Laura Rinaldi, Rossella Delle Donne, Maria Sepe, Omar Torres-Quesada, Daniela Intartaglia, Corrado Garbi, Luigi Insabato, Margherita Santoriello, Verena A. Bachmann, Matthis Synofzik, Herbert H. Lindner, Ivan Conte, Eduard Stefan and Antonio Feliciello ()
Additional contact information
Monia Porpora: University ‘Federico II’
Simona Sauchella: University ‘Federico II’
Laura Rinaldi: University ‘Federico II’
Rossella Delle Donne: University ‘Federico II’
Maria Sepe: University ‘Federico II’
Omar Torres-Quesada: University of Innsbruck
Daniela Intartaglia: Telethon Institute of Genetics and Medicine
Corrado Garbi: University ‘Federico II’
Luigi Insabato: University Federico II
Margherita Santoriello: University ‘Federico II’
Verena A. Bachmann: University of Innsbruck
Matthis Synofzik: University of Tübingen and German Center for Neurodegenerative Diseases (DZNE)
Herbert H. Lindner: Biocenter Medical University of Innsbruck
Ivan Conte: Telethon Institute of Genetics and Medicine
Eduard Stefan: University of Innsbruck
Antonio Feliciello: University ‘Federico II’

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract The primary cilium emanates from the cell surface of growth-arrested cells and plays a central role in vertebrate development and tissue homeostasis. The mechanisms that control ciliogenesis have been extensively explored. However, the intersection between GPCR signaling and the ubiquitin pathway in the control of cilium stability are unknown. Here we observe that cAMP elevation promotes cilia resorption. At centriolar satellites, we identify a multimeric complex nucleated by PCM1 that includes two kinases, NEK10 and PKA, and the E3 ubiquitin ligase CHIP. We show that NEK10 is essential for ciliogenesis in mammals and for the development of medaka fish. PKA phosphorylation primes NEK10 for CHIP-mediated ubiquitination and proteolysis resulting in cilia resorption. Disarrangement of this control mechanism occurs in proliferative and genetic disorders. These findings unveil a pericentriolar kinase signalosome that efficiently links the cAMP cascade with the ubiquitin-proteasome system, thereby controlling essential aspects of ciliogenesis.

Date: 2018
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DOI: 10.1038/s41467-018-03643-9

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