Rab38 and Rab32 control post-Golgi trafficking of melanogenic enzymes.
A mutation in the small GTPase Rab38 gives rise to the mouse coat color phenotype "chocolate" (cht), implicating Rab38 in the regulation of melanogenesis. However, its role remains poorly characterized. We report that cht Rab38(G19V) is inactive and that the nearly normal pigmentation in cht melanocytes results from functional compensation by the closely related Rab32. In cht cells treated with Rab32-specific small interfering RNA, a dramatic loss of pigmentation is observed. In addition to mature melanosomes, Rab38 and Rab32 localize to perinuclear vesicles carrying tyrosinase and tyrosinase-related protein 1, consistent with a role in the intracellular sorting of these proteins. In Rab38/Rab32-deficient cells, tyrosinase appears to be mistargeted and degraded after exit from the trans-Golgi network (TGN). This suggests that Rab38 and Rab32 regulate a critical step in the trafficking of melanogenic enzymes, in particular, tyrosinase, from the TGN to melanosomes. This work identifies a key role for the Rab38/Rab32 subfamily of Rab proteins in the biogenesis of melanosomes and potentially other lysosome-related organelles.
Wasmeier
Christina
C
Molecular and Cellular Medicine, Division of Biomedical Sciences, Imperial College London, London SW7 2AZ, England, UK.
Romao
Maryse
M
Plowright
Lynn
L
Bennett
Dorothy C
DC
Raposo
Graça
G
Seabra
Miguel C
MC
D000818:Animals; D002478:Cells, Cultured; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D016086:Lentivirus / Q000235:genetics; D008543:Melanins / Q000378:metabolism; D020460:Melanosomes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D009154:Mutation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D013347:Subcellular Fractions; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D021601:trans-Golgi Network
D008543:Melanins; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse; D014442:Monophenol Monooxygenase; C466094:Rab32 protein, human; C498786:Rab38 protein, mouse; C498787:Rab38 protein, rat; D020691:rab GTP-Binding Proteins