title: Accumulation of the Raf-1 kinase inhibitory protein (Rkip) is associated with Cep290-mediated photoreceptor degeneration in ciliopathies.
abstract: Primary cilia regulate polarized protein trafficking in photoreceptors, which are dynamic and highly compartmentalized sensory neurons of retina. The ciliary protein Cep290 modulates cilia formation and is frequently mutated in syndromic and non-syndromic photoreceptor degeneration. However, the underlying mechanism of associated retinopathy is unclear. Using the Cep290 mutant mouse rd16 (retinal degeneration 16), we show that Cep290-mediated photoreceptor degeneration is associated with aberrant accumulation of its novel interacting partner Rkip (Raf-1 kinase inhibitory protein). This effect is phenocopied by morpholino-mediated depletion of cep290 in zebrafish. We further demonstrate that ectopic accumulation of Rkip leads to defective cilia formation in zebrafish and cultured cells, an effect mediated by its interaction with the ciliary GTPase Rab8A. Our data suggest that Rkip prevents cilia formation and is associated with Cep290-mediated photoreceptor degeneration. Furthermore, our results indicate that preventing accumulation of Rkip could potentially ameliorate such degeneration.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor,Michigan 48105, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Murga-Zamalloa
authors.forename: Amiya K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Patil
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Reed
authors.forename: Lan Sze
authors.initials: LS
authors.lastname: Chan
authors.forename: Supriya
authors.initials: S
authors.lastname: Davuluri
authors.forename: Johan
authors.initials: J
authors.lastname: Peränen
authors.forename: Toby W
authors.initials: TW
authors.lastname: Hurd
authors.forename: Rivka A
authors.initials: RA
authors.lastname: Rachel
authors.forename: Hemant
authors.initials: H
authors.lastname: Khanna
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002522:Chlorocebus aethiops; D002923:Cilia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002925:Ciliary Motility Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003598:Cytoskeletal Proteins; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; C559615:CEP290 protein, zebrafish; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; C513600:Cep290 protein, mouse; D003598:Cytoskeletal Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; C546061:Rab8a protein, mouse; C539308:Raf kinase inhibitory protein, mouse; D029961:Zebrafish Proteins; C569404:Rab8a protein, zebrafish; C082377:RAB8A protein, human; D020691:rab GTP-Binding Proteins