Cullin 1 (CUL1) Promotes Primary Ciliogenesis through the Induction of Ubiquitin-Proteasome-Dependent Dvl2 Degradation.

Sun-Ok Kim,Kyung Ho Lee,Kyoung Sang Cho,Bo Yeon Kim

doi:10.3390/ijms22147572

Abstract

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.

Highlights

Primary cilia are nonmotile cilia and are structures that function as cellular antennae found on the cell surface [1,2]
To identify novel dishevelled 2 (Dvl2) interacting proteins, Flag-Dvl2-overexpressing cells were immunoprecipitated by an anti-Flag antibody, and coimmunoprecipitated proteins were identified by liquid chromatography (LC)–tandem-mass spectrometry (MS/MS; Figure 1A)
This study identified a novel function of Cullin 1 (CUL1), which ubiquitinylates Dvl2 and promotes primary ciliogenesis

Summary

Introduction

Primary cilia are nonmotile cilia and are structures that function as cellular antennae found on the cell surface [1,2]. The functions of Wnt signaling related to centrosomal proteins in primary cilia assembly and disassembly have been reported recently [2,5,6]. The critical role of protein degradation at the centrosome in primary cilia regulation has been reported. Some protein kinases, such as tau tubulin kinase 2 (TTBK2) and microtubule affinity regulating kinase 4 (MARK4), play a role in inducing cilia formation by removing CP110 from mother centriole [7,8,9]. A subset of ubiquitin E3 ligase, including von Hippel-Lindau protein (pVHL) and mindbomb E3 ubiquitin protein ligase 1

Methods

Results

Conclusion