Rab GTPases: Key players in melanosome biogenesis, transport, and transfer

Abstract

Melanosomes are specialized intracellular organelles that produce and store melanin pigments in melanocytes, which are present in several mammalian tissues and organs, including the skin, hair, and eyes. Melanosomes form and mature stepwise (stages I–IV) in melanocytes and then are transported toward the plasma membrane along the cytoskeleton. They are subsequently transferred to neighboring keratinocytes by a largely unknown mechanism, and incorporated melanosomes are transported to the perinuclear region of the keratinocytes where they form melanin caps. Melanocytes also extend several dendrites that facilitate the efficient transfer of the melanosomes to the keratinocytes. Since the melanosome biogenesis, transport, and transfer steps require multiple membrane trafficking processes, Rab GTPases that are conserved key regulators of membrane traffic in all eukaryotes are crucial for skin and hair pigmentation. Dysfunctions of two Rab isoforms, Rab27A and Rab38, are known to cause a hypopigmentation phenotype in human type 2 Griscelli syndrome patients and in chocolate mice (related to Hermansky–Pudlak syndrome), respectively. In this review article, I review the literature on the functions of each Rab isoform and its upstream and downstream regulators in mammalian melanocytes and keratinocytes.

Alpha-Synuclein and Its Role in Melanocytes

“…This is in agreement with studies in PD, describing that aSyn not only results in a loss of dopaminergic neurons [81] but also impairs the axonal transport of synaptic vesicles [79]. Mature melanosomes are transported from the perinuclear region to the periphery of melanocytes via the transport complex of RAB27A-melanophilin-myosin Va on the actin filament [21,82,83]. We, therefore, concentrated on the direct impact of aSyn on RAB27A but found no change after siSNCA treatment.…”

“…Mature melanosomes travel intracellularly along microtubule tracks and attach to the distal actin cytoskeleton via binding proteins including RAB27A (Ras-related protein RAB-27A). These transport complexes travel to the peripheral regions of the cell, the melanocytic dendrites, and accumulate at the distal tips [13,20,21]. The process of melanin secretion and uptake by the surrounding keratinocytes is still not well understood and discussed controversially [14,20,22,23].…”

Serotonin (5-HT) 2A Receptor Involvement in Melanin Synthesis and Transfer via Activating the PKA/CREB Signaling Pathway

“…As the results shown, dendritic number and length of B16F10 cells were increased because of DOI ( Figure 6 a–c) or TCB-2 ( Figure S6a–c ) treatment. The Western blot experiments revealed that the expression of proteins related to melanosome organization (GP100), melanosome transport (RAB7, RAB17, and RAB27), and melanocyte dendrites (RAC1 and CDC42) were increased in B16F10 cells with DOI ( Figure 6 d) or TCB-2 ( Figure S6d ) treatment [ 24 ]. Immunofluorescent staining of phalloidin showed an increase in cytoskeleton and dendrites with the DOI ( Figure 6 e) or TCB-2 ( Figure S6e ) treatment.…”

The Function of Autophagy as a Regulator of Melanin Homeostasis

“…In one study, ULK1 knockdown in MNT-1 cells increased MITF expression, resulting in upregulation of melanogenesis (Figure 3a) [75]. Numerous proteins are involved in melanogenesis stage II, i.e., the melanosome biogenesis and maturation stage, including adaptor protein (AP)-1, AP-2, biogenesis of lysosome-related organelle complex (BLOC)-1, BLOC-2, BLOC-3, and various Rab GTPases [76][77][78][79][80]. UVRAG, identified as a beclin-1-binding autophagy-associated protein [81,82], has specialized functions in melanosome biosynthesis through its interaction with BLOC-1.…”