Accumulation of the Raf-1 kinase inhibitory protein (Rkip) is associated with Cep290-mediated photoreceptor degeneration in ciliopathies

Carlos A Murga-Zamalloa, Amiya K Ghosh, Suresh B Patil, Nathan A Reed, Lan Sze Chan, Supriya Davuluri, Johan Peränen, Toby W Hurd, Rivka A Rachel, Hemant Khanna

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)28276-86
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number32
DOIs
Publication statusPublished - 12 Aug 2011

Keywords

  • Animals
  • Antigens, Neoplasm
  • Cercopithecus aethiops
  • Cilia
  • Ciliary Motility Disorders
  • HEK293 Cells
  • Humans
  • Mice
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • Phosphatidylethanolamine Binding Protein
  • Retinal Degeneration
  • Zebrafish
  • Zebrafish Proteins
  • rab GTP-Binding Proteins

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