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: 10.37). 09/2008; 15(2):187-97. DOI: 10.1016/j.devcel.2008.07.004
Source: PubMed

ABSTRACT 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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    • "ur studies ) , Polycystin 1 and fibrocystin ( Follit et al . , 2010 ; Ward et al . , 2011 ) , ( ii ) the BBSome complex affected by mutations causing the Bardet – Biedel Syndrome ( Nachury et al . , 2007 ) , ( iii ) RPGR , which is mutated in XLRP ( Murga - Zamalloa et al . , 2010 ) and ( iv ) CEP - 290 ( Kim , Krish - naswami , & Gleeson , 2008 ; Tsang et al . , 2008 ) that organizes NPHP , MKS and JBTS complexes at the transition zone , where they restrict the diffusion of membrane proteins across the ciliary base ( Craige et al . , 2010 ; Garcia - Gonzalo et al . , 2011 ; Sang et al . , 2011 ; van Ree - uwijk , Arts , & Roepman , 2011 ) . Mutations in NPHP , MKS and JBTS proteins cause nephronopht"
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    • "This sequestration phenotype was specific to centriolar satellite proteins, as Cep72 overexpression did not affect the localization of other centrosomal proteins (γ-tubulin and centrin, Figure 4B; pericentrin, ninein, and dynein, Supplemental Figure S7C). We also observed sequestration of Rab8-GFP in Cep72 aggregates in some cells, consistent with the reported interaction of Cep290 and Rab8 (Supplemental Figure S7C; Nachury et al., 2007; Kim et al., 2008; Tsang et al., 2008). Cep72-GFP aggregates that formed in cells depleted of PCM1 were still able to sequester Cep290 but not BBS4, suggesting that Cep72 and Cep290 can interact in the absence of PCM1 (Figure 4D). "
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