Abstract
Melanosomes are lysosome-related organelles in melanocytes that are transported from the perinucleus to the cell periphery by coordination between bidirectional (anterograde and retrograde) microtubule-dependent transport and unidirectional actin-dependent transport. Although the molecular machineries that mediate retrograde transport and actin-dependent transport have already been identified, little is known about the anterograde transport complex on microtubules in mammalian cells. Here we discovered that small GTPase Rab1A on melanosomes recruits SKIP/PLEKHM2 as a Rab1A-specific effector and that Rab1A, SKIP, and a kinesin-1/(Kif5b+KLC2) motor form a transport complex that mediates anterograde melanosome transport in melanocytes. Interestingly, Arl8, Arf-like small GTPase that also interacts with SKIP, is specifically localized at lysosomes and regulates their anterograde transport in melanocytes. Our findings suggest that the anterograde microtubule-dependent transport of melanosomes and lysosomes are differently regulated by independent cargo receptors, i.e., Rab1A and Arl8, respectively, but that a SKIP–kinesin-1 mechanism is responsible for the transport of both.
Highlights
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
We initially hypothesized that Rab1A directly interacts with the tail domain of certain kinesin superfamily proteins (Kifs) for two reasons, first, because the tail domain of some Kifs has been shown to directly interact with certain Rabs, e.g., Kif20A/Rabkinesin-6 with Rab6A/B19, Kif16B with Rab1420 and Kif13A with Rab1121 and, second, because the tail domain of most Kifs contains coiled-coil domains, which often serve as Rab-binding sites[22]
We concluded that Kif proteins themselves are unlikely to function as Rab1A effectors during anterograde melanosome transport in melanocytes
Summary
During the past few decades, a variety of key factors involved in melanosome transport have been identified by genetic analyses of patients with albinism and of coat color mutant mice[2,4,5,6] Functional analyses of these factors have revealed the molecular mechanisms of actin-dependent and microtubule-dependent retrograde melanosome transport. We report finding that Rab1A indirectly recruits the kinesin[1] motor (composed of two Kif5b heavy chains and two light chains) to mature melanosomes through interaction with a Rab1A effector molecule, SKIP (SifA and kinesin-interacting protein, known as PLEKHM2), which was previously characterized as a kinesin-1 and Arl[8] binding protein involved in lysosome transport toward the cell periphery[17,18]. Based on our findings below we discuss the possible mechanisms by which a SKIP–kinesin-1 complex differentially transports two related types of organelles, melanosomes, which are LROs, and lysosomes, in melanocytes
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