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Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
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Vesicle budding is orchestrated by distinct cytosolic proteins such as adaptor proteins, coat proteins, and GTPases. To initiate vesicle budding, membrane-bending proteins containing crescent-shaped BAR domains bind to the lipid heads in the bilayer and distort the membrane to form a protein-coated vesicle bud. Adaptors proteins such as AP2 for clathrin-coated vesicles can nucleate on the deformed membrane. Finally, coat proteins such as clathrin or COPI and COPII assemble into a coat forming...
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The recycling endosome, also known as the endosomal recycling compartment (ERC), is a part of the slow-recycling process of the endocytic pathway. Molecules internalized through receptor-mediated endocytosis are either degraded in the lysosomes or are recycled to the plasma membrane through the fast- or slow-recycling route.
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Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
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Dawn and dusk peaks of outer segment phagocytosis, and visual cycle function require Rab28.

Ailís L Moran1,2, Stephen P Carter1,2, Joanna J Kaylor3

  • 1UCD School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|April 26, 2022
PubMed
Summary

Rab28 protein is crucial for photoreceptor outer segment phagocytosis (OSP) in both dawn and dusk cycles, impacting vision and inherited blindness. Restoring Rab28 in cone cells can correct OSP defects and support the visual cycle.

Keywords:
Rab28bisretinoidsciliaciliopathycone-rod dystrophyouter segmentphagocytosisretinoidsvisual cyclezebrafish

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Area of Science:

  • Cell Biology
  • Genetics
  • Ophthalmology

Background:

  • RAB28 is a ciliary G-protein linked to autosomal recessive cone-rod dystrophy (CRD), a cause of inherited blindness.
  • Loss of Rab28 in animal models impairs photoreceptor outer segment phagocytosis (OSP), particularly at dawn.

Purpose of the Study:

  • To investigate the role of Rab28 in both dawn and dusk OSP.
  • To elucidate the molecular mechanisms underlying Rab28-associated CRD.
  • To assess the impact of Rab28 on the visual cycle and retinoid metabolism.

Main Methods:

  • Utilized zebrafish models with Rab28 knockout (KO) and transgenic overexpression.
  • Performed proteomic profiling to identify dysregulated factors in Rab28-deficient retinas.
  • Measured retinoid levels (11-cRAL, 11cRP, atRP) in larval and adult KO fish.

Main Results:

  • Rab28 is essential for dusk OSP peaks, not just basal levels.
  • Proteomic analysis revealed dysregulation of eye-specific factors and OSP-related proteins in rab28 KO fish.
  • Transgenic Rab28 expression in cones rescued OSP defects in KO fish.
  • Rab28 deficiency significantly reduced key retinoid levels, impacting the visual cycle.

Conclusions:

  • Rab28 plays a critical role in both dawn and dusk OSP, essential for photoreceptor health.
  • Rab28 is implicated in vitamin A metabolism and retinoid recycling within the retina.
  • Gene replacement therapy targeting cone photoreceptors shows potential for treating RAB28-associated CRD.