ARL3 regulates trafficking of prenylated phototransduction proteins to the rod outer segment

Hum Mol Genet. 2016 May 15;25(10):2031-2044. doi: 10.1093/hmg/ddw077. Epub 2016 Mar 2.

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.

MeSH terms

  • ADP-Ribosylation Factors / biosynthesis
  • ADP-Ribosylation Factors / genetics*
  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / biosynthesis
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / genetics
  • Eye Proteins / biosynthesis
  • Eye Proteins / genetics
  • G-Protein-Coupled Receptor Kinase 1 / biosynthesis
  • G-Protein-Coupled Receptor Kinase 1 / genetics
  • GTP-Binding Proteins
  • Gene Expression Regulation
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / pathology
  • Humans
  • Membrane Proteins
  • Mice
  • Mice, Transgenic
  • Protein Prenylation / genetics
  • Pyrophosphatases / genetics*
  • Retina / metabolism
  • Retina / pathology
  • Retinal Rod Photoreceptor Cells / metabolism
  • Retinal Rod Photoreceptor Cells / pathology
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / pathology
  • Rod Cell Outer Segment / metabolism
  • Rod Cell Outer Segment / pathology

Substances

  • Eye Proteins
  • Membrane Proteins
  • RP2 protein, mouse
  • G-Protein-Coupled Receptor Kinase 1
  • Grk1 protein, mouse
  • Cyclic Nucleotide Phosphodiesterases, Type 6
  • Pde6a protein, mouse
  • GTP-Binding Proteins
  • Pyrophosphatases
  • Arl3 protein, mouse
  • ADP-Ribosylation Factors