Rab7 and Rab27a control two motor protein activities involved in melanosomal transport

Abstract

Melanosomes are lysosome-related organelles that synthesize, store and transport melanin. In epidermal melanocytes, melanosomes mature and are transferred to surrounding keratinocytes, which is essential for skin and coat colour. Mouse coat colour mutants reveal a critical role for the small GTPase Rab27a, which recruits myosin Va through its effector protein melanophilin/Slac2a. Here we have studied how two different Rab GTPases control two motor proteins during subsequent phases in transport of melanosomes. We show that the small GTPase Rab7 mainly associates with early and intermediate stage melanosomes and Rab27a to intermediate and mature melanosomes. Rab27a is found in an active state on mature melanosomes in the tips of the dendrites. The Rab7-Rab7-interacting lysosomal protein-dynein pathway only controls early and intermediate stage melanosomes because the mature melanosomes lack Rab7 and associate with the actin network through Rab27a recruited MyoVa. Thus two Rab proteins regulate two different motor proteins, thereby controlling complementary phases in melanosome biogenesis: Rab7 controls microtubule-mediated transport of early and Rab27a the subsequent actin-dependent transport of mature melanosomes.

Myosin Vc Interacts with Rab32 and Rab38 Proteins and Works in the Biogenesis and Secretion of Melanosomes

“…The lack of interaction of Myosin Vc with Rab11 or Rab17 suggests the function ascribed to these Rabs in melanosome secretion is independent of Myosin Vc. Another pair of relevant Rabs is that of Rab7a and Rab8a, which in melanocytes localize to immature and mature melanosomes, respectively (66,67). In this context the interaction between these Rabs and Myosin Vc (Fig.…”

“…In melanocytes, Rab7a localizes to immature stage I-III melanosomes and Rab8a to more mature, pigmented melanosomes and may be involved in melanosome biogenesis (66,67). Therefore, we tested for interaction between the constitutively active, GTP-locked mutant version of these Rabs and Myosin Vc as well as Myosin Va and Myosin Vb (Fig.…”

Cargo binding activates myosin VIIA motor function in cells

“…Because Rab27a associates with membrane vesicles with its geranyl-geranyl moiety, it is thought that the MyRip/Rab27a complex links myosin VIIA to membrane vesicles, such as premature melanosomes, in ARPE-19 cells. It should be noted that, although ARPE-19 cells do not make mature melanosomes containing melanin (32), Rab27a is present at stages of melanosome maturation (33), which facilitates the translocation of myosin VIIA/cargo complex to the filopodial tips. Because a myosin VIIA forced dimer, but not monomer, can move toward filopodial tips, it is reasonable to assume that the production of myosin VIIA/MyRip/Rab27a ternary complex and its association with membrane vesicles induces dimer formation, thus activating the movement of myosin VIIA/cargo complex in cells.…”

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

“…Microtubule dependent bidirectional movement of melanosomes requires a functional MEK-ERK complex on melanosomes bound by an unknown scaffold molecule [175,176]. The small GTPases, Rab7, Rab8 and Rab27, through their interaction with motors, have been implicated in melanosome movement [177][178][179][180][181][182] and a few Rabs are targets for ERK phosphorylation [183], raising the possibility that ERK signaling may influence Rab functions necessary for melanosome traffic. ERK dependent traffic of melanosomes is regulated by minus end directed dynein motors, that raised the speculation that ERK may directly regulate dynein activity [184] and thereby influence intracellular mobility of signaling complexes and organelles.…”