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. Author manuscript; available in PMC: 2020 Aug 1.
Published in final edited form as: Curr Opin Cell Biol. 2019 Jun 22;59:147–158. doi: 10.1016/j.ceb.2019.05.003

Figure 2.

Figure 2.

Model of membrane dynamics during melanosome biogenesis. Shown are pathways of membrane transport from the Golgi and early endosomes to generate different stages of melanosomes. Melanosomes mature from stage I (equivalent to vacuolar domain of a sorting early endosome) to stage IV by progressive acquisition of protein cargoes, mirrored by morphological changes. Following clathrin-dependent endocytosis from the plasma membrane, PMEL is targeted to stage I melanosomes within which it forms fibrils, with the assistance of CD63 and ApoE, on intraluminal vesicles (white circles). The fibrils then mature to fully assembled sheets in stage II in a process requiring collisions with lysosomes mediated by PIKFyve (thick arrow). Melanin synthesis begins upon acquisition of Tyrosinase (TYR), additional enzymes (e.g. TYRP1 and DCT), and transporters that neutralize the luminal pH. The newly generated melanin accumulates on the sheets in stage III and throughout the organelle in stage IV. Cargo transport from endosomes occurs by an AP-3-dependent vesicular pathway taken by TYR and a tubular pathway taken by TYRP1 and other cargoes that requires BLOC-1, RAB22A, AP-1 and KIF13A for membrane tubule formation along microtubules (Box 1), BLOC-2 for targeting to maturing stage III melanosomes, and the vSNARE VAMP7 for fusion with melanosomes. An additional pathway to target DCT and MART-1 to melanosomes from the Golgi requires RAB6 for vesicle formation and its effector ELKS for docking to melanosomes (Box 2). VAMP7 is recycled from melanosomes in tubules that require RAB38, its GEF BLOC-3, and the scaffold protein VARP for formation and/ or VAMP7 incorporation, and that require Myosin VI, optineurin, the WASH complex, Arp2/3 and actin for tubule constriction, scission and release (Box 3); the target organelle for these tubules remains speculative (dashed arrow). Mature stage IV melanosomes in skin melanocytes are captured in the periphery by the RAB27A/ Melanophilin/ Myosin Va complex, and may fuse with the plasma membrane in a RAB11B-dependent manner to release melanocores for uptake by neighbouring keratinocytes.