JB Review Role of Rab family GTPases and their effectors in melanosomal logistics Received January 10, 2012; accepted February 3, 2012; published online February 9, 2012 Norihiko Ohbayashi and Mitsunori Fukuda* Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan *Mitsunori Fukuda, Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan. Tel: þ81-22-795-7731, Fax: þ81-22-795-7733, email: nori@m.tohoku.ac.jp Rab GTPases constitute a family of small GTPases that regulate a variety of membrane trafficking events in all eukaryotic cells by recruiting their specific effector molecules. Recent accumulating evidence indi- cates that members of the mammalian Rab small GTPase family are involved in certain physiological and pathological processes. In particular, functional impairments of specific Rab proteins, e.g. Rab38 and Rab27A, their regulators or their effectors cause pig- mentation disorders in humans and coat colour vari- ations in mice because such impairments cause defects in melanosomal logistics, i.e. defects in melanosome biogenesis and transport. Genetic and biochemical ana- lyses of the gene products responsible for mammalian pigmentation disorders in the past decade have revealed that Rab-mediated endosomal transport systems and melanosome transport systems play crucial roles in the efficient darkening of mammalian hair and skin. In this article, we review current knowledge regarding melanosomal logistics, with particular focus on the roles of Rab small GTPases and their effectors. Keywords: Cellular logistics/melanocyte/membrane traffic/Rab effector/small GTPase. Abbreviations: ABD, actin-binding domain; ANKR, ankyrin repeat; AP, adaptor protein complex; BLOC, biogenesis of lysosome-related organelles complex; dsu, dilute suppressor; GEF, guanine nucleotide exchange factor; HPS, HermanskyPudlak syndrome; MBD, myosin Va-binding domain; MC1R, melano- cortin 1 receptor; Mreg, melanoregulin, MSH, melanocyte-stimulating hormone; REP-1, Rab escort protein-1; RGGT, Rab geranylgeranyl transferase; RILP, Rab7-interacting lysosomal protein; SHD, Slp homology domain; TGN, trans-Golgi network; Tyrp1, tyrosinase-related protein 1; VAMP, vesicle-associated membrane protein; Varp, VPS9-ankyrin-repeat protein; VID, VAMP7-interaction domain; VPS9, vacuolar protein sorting 9. Mammalian epidermal melanocytes are specialized melanin pigment-producing cells that are responsible for protecting the human body from ultraviolet radi- ation, and their disorganized activity often causes hyperpigmentation or albinism. Melanosomes are tissue-specific lysosome-related organelles that synthe- size and store melanin pigments in melanocytes (1). Melanosomes are produced around the nucleus mainly by the endosomal transport systems. Mature melanosomes are transported along two cytoskeletal components, i.e. microtubules and actin filaments, and eventually attached and tethered to the plasma membrane (1). Upon activation, melanocytes are thought to extend dendrites by reorganizing their cyto- skeletons and membranes to efficiently transfer mela- nosomes to neighbouring keratinocytes and hair matrix cells (2). All of these intracellular and intercel- lular transport systems are required for efficient skin and hair pigmentation in mammals. During the past few decades, a variety of key factors involved in the intracellular melanosome transport systems have been identified by genetic analyses of patients with albinism, e.g. patients with HermanskyPudlak syndrome (HPS), Griscelli syn- drome and Che´diakHigashi syndrome, and of coat colour mutant mice (3, 4). It is noteworthy that the key factors include several Rab-type small GTPases and their regulators, indicating that they play crucial roles in melanosome biogenesis and transport (called ‘melanosomal logistics’). Rab small GTPases are the key regulators of diverse membrane trafficking events, including cargo sorting, vesicle budding, ves- icle formation, vesicle transport along the cytoskel- eton and docking, tethering and fusion of vesicles with target membranes in all eukaryotic cells (5, 6). The number of Rab proteins varies from species to species and approximately 60 distinct Rab proteins have been identified in mammals (7). Rab proteins are generally thought to function as molecular switches that shuttle between a GDP-bound inactive conformation (cytosolic localization) and a GTP- bound active conformation (membranous localiza- tion). The GTP-bound Rab proteins recruit specific effector molecules to specific membrane sites where they function. These effectors then execute diverse Rab-mediated membrane trafficking events described above (5, 6). In this article, we review recent advances in knowledge of the functions of Rab pro- teins, their effectors and their regulators in mamma- lian epidermal melanocytes, with particular focus on the regulatory mechanisms of melanosomal logistics, including biogenesis, transport and transfer of melanosomes. Featured Article J. Biochem. 2012;151(4):343–351 doi:10.1093/jb/mvs009 ß The Authors 2012. Published by Oxford University Press on behalf of the Japanese Biochemical Society. 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