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Crag Is a GEF for Rab11 Required for Rhodopsin Trafficking and Maintenance of Adult Photoreceptor Cells

Authors
Journal
PLoS Biology
1544-9173
Publisher
Public Library of Science
Publication Date
Volume
10
Issue
12
Identifiers
DOI: 10.1371/journal.pbio.1001438
Keywords
  • Research Article
  • Biology
  • Genetics
  • Genetic Mutation
  • Mutagenesis
  • Animal Genetics
  • Genetic Screens
  • Genetics Of Disease
  • Model Organisms
  • Animal Models
  • Drosophila Melanogaster
  • Molecular Cell Biology
  • Membranes And Sorting
  • Neuroscience
  • Sensory Systems
  • Visual System
  • Neural Homeostasis
  • Neurobiology Of Disease And Regeneration
Disciplines
  • Biology
  • Physics

Abstract

Author Summary Animals sense light through receptors called Rhodopsins. These proteins are typically localized to stacked membranes in photoreceptors. In flies, upon light exposure, Rhodopsin undergoes conformational changes and becomes active as metarhodopsin. Metarhodopsin then initiates a signaling cascade that activates the photoreceptor cell. To deactivate the light response, metarhodopsin is converted back into Rhodopsin by absorption of another photon of light. Under certain conditions, metarhodopsin cannot be converted back to Rhodopsin, and it is then endocytosed and degraded. Rhodopsin then needs to be synthesized and delivered back to the membrane stacks. Here, we show that the Calmodulin-binding protein Crag is required for the delivery of newly made Rhodopsin to the membrane stacks. Loss of Crag leads to the accumulation of Rhodopsin in the cytosol, followed by shrinkage of membrane stack volume, and, eventually, photoreceptor cell degeneration. We also show that Crag activates a target protein, Rab11, which mediates the vesicular transport of Rhodospin to the membrane. Finally, we document that the human homolog of Crag, DENND4A, is able to rescue the loss of Crag in flies, suggesting that DENND4A functions in a similar process in vertebrates.

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