Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 14, Pages -Publisher
MDPI
DOI: 10.3390/ijms22147572
Keywords
Dvl2; CUL1; primary ciliogenesis; ubiquitination; proteolysis
Funding
- National Research Foundation of Korea (NRF) - Korea government (MSIT) [NRF-2021R1A2C1004854, NRF-2021R1A2C3004965]
- R&D Convergence Program of the National Research Council of Science and Technology (NST) of the Republic of Korea [CAP-16-03-KRIBB]
- KRIBB Research Initiative Program [KGM5292113]
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Primary cilia are important cell structures regulated by various cellular signals, abnormal regulation of which is related to human diseases. This study identified a novel regulatory factor CUL1, which induces Dvl2 degradation through ubiquitination to promote ciliogenesis, providing a new therapeutic target for cilia-related diseases.
Primary cilia are nonmotile cellular signal-sensing antenna-like structures composed of microtubule-based structures that distinguish them from motile cilia in structure and function. Primary ciliogenesis is regulated by various cellular signals, such as Wnt, hedgehog (Hh), and platelet-derived growth factor (PDGF). The abnormal regulation of ciliogenesis is closely related to developing various human diseases, including ciliopathies and cancer. This study identified a novel primary ciliogenesis factor Cullin 1 (CUL1), a core component of Skp1-Cullin-F-box (SCF) E3 ubiquitin ligase complex, which regulates the proteolysis of dishevelled 2 (Dvl2) through the ubiquitin-proteasome system. Through immunoprecipitation-tandem mass spectrometry analysis, 176 Dvl2 interacting candidates were identified, of which CUL1 is a novel Dvl2 modulator that induces Dvl2 ubiquitination-dependent degradation. Neddylation-dependent CUL1 activity at the centrosomes was essential for centrosomal Dvl2 degradation and primary ciliogenesis. Therefore, this study provides a new mechanism of Dvl2 degradation by CUL1, which ultimately leads to primary ciliogenesis, and suggest a novel target for primary cilia-related human diseases.
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