Rab9A is required for delivery of cargo from recycling endosomes to melanosomes

• Published in: Pigment cell and melanoma research Vol. 29; no. 1; pp. 43 - 59
• Main Authors: Mahanty, Sarmistha, Ravichandran, Keerthana, Chitirala, Praneeth, Prabha, Jyothi, Jani, Riddhi Atul, Setty, Subba Rao gangi
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.01.2016; Wiley Subscription Services, Inc; John Wiley & Sons, Ltd
• Subjects: Animals; AP-3; BLOC-1; BLOC-2; BLOC-3; Endocytosis; Endosomes - metabolism; Gene Knockdown Techniques; HPS; Lysosomes - metabolism; Melanocytes - metabolism; Melanosomes - metabolism; Mice; Models, Biological; Original; Pigmentation; Protein Transport; rab GTP-Binding Proteins - metabolism; Rab38/Rab32; Rab9A; RNA, Small Interfering - metabolism; BLOC-2; BLOC-1; BLOC-3; HPS; Rab9A; AP-3; Rab38/Rab32
• ISSN: 1755-1471; 1755-148X
• DOI: 10.1111/pcmr.12434

Summary Melanosomes are a type of lysosome‐related organelle that is commonly defective in Hermansky–Pudlak syndrome. Biogenesis of melanosomes is regulated by BLOC‐1, ‐2, ‐3, or AP‐1, ‐3 complexes, which mediate cargo transport from recycling endosomes to melanosomes. Although several Rab GTPases have been shown to regulate these trafficking steps, the precise role of Rab9A remains unknown. Here, we found that a cohort of Rab9A associates with the melanosomes and its knockdown in melanocytes results in hypopigmented melanosomes due to mistargeting of melanosomal proteins to lysosomes. In addition, the Rab9A‐depletion phenotype resembles Rab38/32‐inactivated or BLOC‐3‐deficient melanocytes, suggesting that Rab9A works in line with BLOC‐3 and Rab38/32 during melanosome cargo transport. Furthermore, silencing of Rab9A, Rab38/32 or its effector VARP, or BLOC‐3‐deficiency in melanocytes decreased the length of STX13‐positive recycling endosomal tubules and targeted the SNARE to lysosomes. This result indicates a defect in directing recycling endosomal tubules to melanosomes. Thus, Rab9A and its co‐regulatory GTPases control STX13‐mediated cargo delivery to maturing melanosomes.