CP110 Suppresses Primary Cilia Formation through Its Interaction with CEP290, a Protein Deficient in Human Ciliary Disease

Department of Pathology and Cancer Institute, New York University School of Medicine, 522 1(st) Avenue, New York, NY 10016, USA.
Developmental Cell (Impact Factor: 9.71). 09/2008; 15(2):187-97. DOI: 10.1016/j.devcel.2008.07.004
Source: PubMed


Primary cilia are nonmotile organelles implicated in signaling and sensory functions. Understanding how primary cilia assemble could shed light on the many human diseases caused by mutations in ciliary proteins. The centrosomal protein CP110 is known to suppress ciliogenesis through an unknown mechanism. Here, we report that CP110 interacts with CEP290--a protein whose deficiency is implicated in human ciliary disease--in a discrete complex separable from other CP110 complexes involved in regulating the centrosome cycle. Ablation of CEP290 prevents ciliogenesis without affecting centrosome function or cell-cycle progression. Interaction with CEP290 is absolutely required for the ability of CP110 to suppress primary cilia formation. Furthermore, CEP290 and CP110 interact with Rab8a, a small GTPase required for cilia assembly. Depletion of CEP290 interferes with localization of Rab8a to centrosomes and cilia. Our results suggest that CEP290 cooperates with Rab8a to promote ciliogenesis and that this function is antagonized by CP110.

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Available from: William Y Tsang, Jan 04, 2014
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    • "The Cep97 protein is required to target CP110 to this distal part of the centriole and overexpression of these proteins can prevent the formation of primary cilia in RPE1 cells (Spektor et al. 2007; Tsang et al. 2008). This is suggested to occur by opposing CEP290, whose depletion prevents ciliogenesis , by interfering with Rab8a's localization to centrosomes and cilia (Tsang et al. 2008). Depletion of a kinesin-13 subfamily member, Kif24, also induces the formation of primary cilia, but not elongated centrioles, apparently by displacing CP110 and Cep97 from the mother centriole (Kobayashi et al. 2011). "
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    ABSTRACT: The centrosome was discovered in the late 19th century when mitosis was first described. Long recognized as a key organelle of the spindle pole, its core component, the centriole, was realized more than 50 or so years later also to comprise the basal body of the cilium. Here, we chart the more recent acquisition of a molecular understanding of centrosome structure and function. The strategies for gaining such knowledge were quickly developed in the yeasts to decipher the structure and function of their distinctive spindle pole bodies. Only within the past decade have studies with model eukaryotes and cultured cells brought a similar degree of sophistication to our understanding of the centrosome duplication cycle and the multiple roles of this organelle and its component parts in cell division and signaling. Now as we begin to understand these functions in the context of development, the way is being opened up for studies of the roles of centrosomes in human disease. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor Perspectives in Medicine 02/2015; 7(1-2). DOI:10.1101/cshperspect.a015800 · 9.47 Impact Factor
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    • "While the precise function of Cep97 awaits further experimentation, this protein might serve as a chaperone to stabilize CP110, allowing the co-recruitment of both proteins to the centrosome. CP110, on the other hand, is thought to impose a structural role at the centrosome and forms discrete complexes critical for cell cycle regulation and cilia assembly (Figure 1) [23,25-31]. This protein does not have an associated enzymatic activity; rather, it was shown to localize to the distal ends of centrioles, forming a ‘cap’ above the growing microtubules that could restrain microtubule growth [32]. "
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    ABSTRACT: Cilia are hair-like protrusions found at the surface of most eukaryotic cells. They can be divided into two types, motile and non-motile. Motile cilia are found in a restricted number of cell types, are generally present in large numbers, and beat in a coordinated fashion to generate fluid flow or locomotion. Non-motile or primary cilia, on the other hand, are detected in many different cell types, appear once per cell, and primarily function to transmit signals from the extracellular milieu to the cell nucleus. Defects in cilia formation, function, or maintenance are known to cause a bewildering set of human diseases, or ciliopathies, typified by retinal degeneration, renal failure and cystic kidneys, obesity, liver dysfunction, and neurological disorders. A common denominator between motile and primary cilia is their structural similarity, as both types of cilia are composed of an axoneme, the ciliary backbone that is made up of microtubules emanating from a mother centriole/basal body anchored to the cell membrane, surrounded by a ciliary membrane continuous with the plasma membrane. This structural similarity is indicative of a universal mechanism of cilia assembly involving a common set of molecular players and a sophisticated, highly regulated series of molecular events. In this review, we will mainly focus on recent advances in our understanding of the regulatory mechanisms underlying cilia assembly, with special attention paid to the centriolar protein, CP110, its interacting partner Cep290, and the various downstream molecular players and events leading to intraflagellar transport (IFT), a process that mediates the bidirectional movement of protein cargos along the axoneme and that is essential for cilia formation and maintenance.
    Cilia 07/2013; 2(1):9. DOI:10.1186/2046-2530-2-9
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    • "Cep290 is a 290 kDa protein that is localised at the centrosome [3], [36], [42], [51]. To examine whether Ahi1 is necessary for correct recruitment of Cep290 to centrosomes [52], [53], we ablated Ahi1 expression using siRNA in IMCD3 renal epithelial cells [49] and visualised Cep290 and centrosomes using anti-Cep290 and anti-gamma tubulin immunofluorescence. "
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    ABSTRACT: Joubert syndrome and related diseases (JSRD) are developmental cerebello-oculo-renal syndromes with phenotypes including cerebellar hypoplasia, retinal dystrophy and nephronophthisis (a cystic kidney disease). We have utilised the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR), to perform in-situ hybridisation studies on embryonic tissues, revealing an early onset neuronal, retinal and renal expression pattern for AHI1. An almost identical pattern of expression is seen with CEP290 in human embryonic and fetal tissue. A novel finding is that both AHI1 and CEP290 demonstrate strong expression within the developing choroid plexus, a ciliated structure important for central nervous system development. To test if AHI1 and CEP290 may have co-evolved, we carried out a genomic survey of a large group of organisms across eukaryotic evolution. We found that, in animals, ahi1 and cep290 are almost always found together; however in other organisms either one may be found independent of the other. Finally, we tested in murine epithelial cells if Ahi1 was required for recruitment of Cep290 to the centrosome. We found no obvious differences in Cep290 localisation in the presence or absence of Ahi1, suggesting that, while Ahi1 and Cep290 may function together in the whole organism, they are not interdependent for localisation within a single cell. Taken together these data support a role for AHI1 and CEP290 in multiple organs throughout development and we suggest that this accounts for the wide phenotypic spectrum of AHI1 and CEP290 mutations in man.
    PLoS ONE 09/2012; 7(9):e44975. DOI:10.1371/journal.pone.0044975 · 3.23 Impact Factor
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