title: ARL3 regulates trafficking of prenylated phototransduction proteins to the rod outer segment.
abstract: The small GTPase, ADP-ribosylation factor-like 3 (ARL3), has been proposed to participate in the transport of proteins in photoreceptor cells. Moreover, it has been implicated in the pathogenesis associated with X-linked retinitis pigmentosa (XLRP) resulting from mutations in the ARL3 GTPase activating protein, retinitis pigmentosa 2 (RP2). To determine the importance of ARL3 in rod photoreceptor cells, we generated transgenic mice expressing a dominant active form of ARL3 (ARL3-Q71L) under a rod-specific promoter. ARL3-Q71L animals exhibited extensive rod cell death after post-natal day 30 (PN30) and degeneration was complete by PN70. Prior to the onset of cell death, rod photoresponse was significantly reduced along with a robust decrease in rod phosphodiesterase 6 (PDE6) and G-protein receptor kinase-1 (GRK1) levels. Furthermore, assembled phosphodiesterase-6 (PDE6) subunits, rod transducin and G-protein receptor kinase-1 (GRK1) accumulated on large punctate structures within the inner segment in ARL3-Q71L retina. Defective trafficking of prenylated proteins is likely due to sequestration of prenyl binding protein δ (PrBPδ) by ARL3-Q71L as we demonstrate a specific interaction between these proteins in the retina. Unexpectedly, our studies also revealed a novel role for ARL3 in the migration of photoreceptor nuclei. In conclusion, this study identifies ARL3 as a key player in prenylated protein trafficking in rod photoreceptor cells and establishes the potential role for ARL3 dysregulation in the pathogenesis of RP2-related forms of XLRP.
authors.affiliation: Department of Ophthalmology.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Wright
authors.affiliation: Department of Ophthalmology.
authors.forename: Ratnesh K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Department of Ophthalmology.
authors.forename: Ryan
authors.initials: R
authors.lastname: Alpino
authors.affiliation: Eye Research Institute, Oakland University, Rochester, MI 48309, USA.
authors.forename: Andrew F X
authors.initials: AF
authors.lastname: Goldberg
authors.affiliation: Department of Ophthalmology, Department of Biochemistry and Center for Neuroscience, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WA 26506, USA and.
authors.forename: Maxim
authors.initials: M
authors.lastname: Sokolov
authors.affiliation: Department of Ophthalmology, Department of Biochemistry and Center for Neuroscience, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WA 26506, USA and ramamurthyv@wvumedicine.org.
authors.forename: Visvanathan
authors.initials: V
authors.lastname: Ramamurthy
mesh_terms: D020727:ADP-Ribosylation Factors / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000096:biosynthesis / Q000235:genetics; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics; D051606:G-Protein-Coupled Receptor Kinase 1 / Q000096:biosynthesis / Q000235:genetics; D019204:GTP-Binding Proteins; D005786:Gene Expression Regulation; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D017368:Protein Prenylation / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D012374:Rod Cell Outer Segment / Q000378:metabolism / Q000473:pathology
chemical_list: D005136:Eye Proteins; D008565:Membrane Proteins; C508759:RP2 protein, mouse; D051606:G-Protein-Coupled Receptor Kinase 1; C496762:Grk1 protein, mouse; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C498747:Pde6a protein, mouse; D019204:GTP-Binding Proteins; D011755:Pyrophosphatases; C490248:Arl3 protein, mouse; D020727:ADP-Ribosylation Factors