Melanosomes on the move: a model to understand organelle dynamics

Hume, Alistair N.; Seabra, Miguel C.

doi:10.1042/bst0391191

Cited by 81 publications

(89 citation statements)

References 61 publications

(67 reference statements)

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“…30 Its constitutive association with the platelet granule surface might play a role in anchorage of the granules to F-actin network to allow positioning within the mature MK. F-actin networks indeed provide the scaffold for the anchorage and positioning of secretory granules, 20,31,32 and F-actin-disrupting agents in melanocytes have for instance been shown to result in the formation of melanosome aggregates. [33][34][35] We observed here that myosin deficiency modestly but significantly impairs organelle motility within MKs, in terms of mean displacement ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

“…16 Actin filaments serve as "rails" for the myosin-based traveling of organelles, [16][17][18] and as a support for their location and distribution. [19][20][21] We therefore investigated whether the F-actin cytoskeleton was affected by the absence of myosin. Progenitor cells from bone marrow were cultured for 4 days and allowed to adhere to a fibronectin-coated surface.…”

Section: Absence Of Myosin Iia Impairs F-actin Organizationmentioning

confidence: 99%

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Myosin IIA is critical for organelle distribution and F-actin organization in megakaryocytes and platelets

Pertuy

Eckly

Weber

et al. 2014

Blood

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Key Points• Myosin IIA deficiency affects F-actin structuration and organelle distribution in MKs which leads to abnormal platelet organelle content.During proplatelet formation, a relatively homogeneous content of organelles is transported from the megakaryocyte (MK) to the nascent platelets along microtubule tracks. We found that platelets from Myh9 2/2 mice and a MYH9-RD patient were heterogeneous in their organelle content (granules and mitochondria). In addition, Myh9 2/2 MKs have an abnormal cytoplasmic clustering of organelles, suggesting that the platelet defect originates in the MKs. Myosin is not involved in the latest stage of organelle traffic along microtubular tracks in the proplatelet shafts as shown by confocal observations of proplatelet buds. By contrast, it is required for the earlier distribution of organelles within the large MK preplatelet fragments shed into the sinusoid circulation before terminal proplatelet remodeling. We show here that F-actin is abnormally clustered in the cytoplasm of Myh9 2/2 MKs and actin polymerization is impaired in platelets. Myosin IIA is required for normal granule motility and positioning within MKs, mechanisms that may be dependent on organelle traveling and tethering onto F-actin cytoskeleton tracks. Altogether, our results indicate that the distribution of organelles within platelets critically depends on a homogeneous organelle distribution within MKs and preplatelet fragments, which requires myosin IIA. (Blood. 2014;123(8):1261-1269

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Section: Discussionmentioning

confidence: 99%

Section: Absence Of Myosin Iia Impairs F-actin Organizationmentioning

confidence: 99%

Myosin IIA is critical for organelle distribution and F-actin organization in megakaryocytes and platelets

Pertuy

Eckly

Weber

et al. 2014

Blood

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“…However, not much is known about the mechanism of microtubulebased transport in melanocytes, including the contributions of the microtubule-associated motors to the melanosome transport (5,6,(8)(9)(10). In contrast, the actin-based transport of melanosomes has been characterized in greater detail.…”

mentioning

confidence: 99%

Myosin Va’s adaptor protein melanophilin enforces track selection on the microtubule and actin networks in vitro

Oberhofer

Spieler

Rosenfeld

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Pigment organelles, or melanosomes, are transported by kinesin, dynein, and myosin motors. As such, melanosome transport is an excellent model system to study the functional relationship between the microtubule-and actin-based transport systems. In mammalian melanocytes, it is well known that the Rab27a/melanophilin/myosin Va complex mediates actin-based transport in vivo. However, pathways that regulate the overall directionality of melanosomes on the actin/microtubule networks have not yet been delineated. Here, we investigated the role of PKA-dependent phosphorylation on the activity of the actin-based Rab27a/melanophilin/myosin Va transport complex in vitro. We found that melanophilin, specifically its C-terminal actin-binding domain (ABD), is a target of PKA. Notably, in vitro phosphorylation of the ABD closely recapitulated the previously described in vivo phosphorylation pattern. Unexpectedly, we found that phosphorylation of the ABD affected neither the interaction of the complex with actin nor its movement along actin tracks. Surprisingly, the phosphorylation state of melanophilin was instead important for reversible association with microtubules in vitro. Dephosphorylated melanophilin preferred binding to microtubules even in the presence of actin, whereas phosphorylated melanophilin associated with actin. Indeed, when actin and microtubules were present simultaneously, melanophilin's phosphorylation state enforced track selection of the Rab27a/melanophilin/ myosin Va transport complex. Collectively, our results unmasked the regulatory dominance of the melanophilin adaptor protein over its associated motor and offer an unexpected mechanism by which filaments of the cytoskeletal network compete for the moving organelles to accomplish directional transport on the cytoskeleton in vivo.melanophilin | myosin Va | intracellular transport | transport regulation

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“…Interestingly, there is evidence of some functional redundancy between Rab3 and its closest homologues, Rab27A and Rab27B, which are involved in the delivery of vesicles near the exocytic site (Fukuda, 2008;Gomi, et al, 2007;Ostrowski, et al, 2010). Studies of melanosome dynamics have indicated that Rab27A has a role in vesicular recruitment and this is mediated by its interaction with a specific effector called Melanophilin, which in turn binds an actin motor protein, MyosinVa (Hume & Seabra, 2011;Seabra & Coudrier, 2004). There appears to be a further functional divergence of Rabs, where Rab27A and Rab27B control different steps of the secretion pathway (Ostrowski, et al, 2010).…”

Section: Rab Gtpases and Vesicular Tetheringmentioning

confidence: 99%