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Article in Press G Model YSCDB-1564; No. of Pages 10 ARTICLE IN PRESS Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx Contents lists available at ScienceDirect Seminars in Cell & Developmental Biology j ournal homepage: www.elsevier.com/locate/semcdb Review The role of the cytoskeleton and molecular motors in endosomal dynamics 1 1 ∗ ∗∗ Elizabeth Granger , Gavin McNee , Victoria Allan , Philip Woodman Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK a r t i c l e i n f o a b s t r a c t Article history: The endocytic pathway is essential for processes that define how cells interact with their environment, Available online xxx including receptor signalling, cell adhesion and migration, pathogen entry, membrane protein turnover and nutrient uptake. The spatial organisation of endocytic trafficking requires motor proteins that tether Keywords: membranes or transport them along the actin and microtubule cytoskeletons. Microtubules, actin fila- Endosome ments and motor proteins also provide force to deform and assist in the scission of membranes, thereby Lysosome facilitating endosomal sorting and the generation of transport intermediates. Recycling © 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license Dynein Kinesin (http://creativecommons.org/licenses/by/3.0/). Myosin Contents 1. The endosomal system: an overview. 00 2. Motor proteins . 00 3. Uptake from the plasma membrane: the role of actin . 00 4. Transport away from the cell cortex . 00 5. Endosome motility . 00 5.1. The molecular basis for dynein-driven endosome/lysosome motility . 00 5.2. The molecular basis for outward microtubule-based endosome/lysosome motility . 00 5.3. Bidirectional movement of endocytic compartments . 00 6. Endosomal sorting and recycling . 00 7. Transfer to the cell surface . 00 8. Conclusions and significance . 00 Acknowledgements . 00 References . 00 1. The endosomal system: an overview also receives vesicles derived from the TGN. From the endosome, cargo is sorted: for degradation, via a pathway comprised of mul- The early endosome, characterised by the presence of rab5 and tivesicular bodies (MVBs), during which endosomes mature and EEA1, acts as the major sorting station on the endocytic pathway then fuse with the lysosome; or for recycling back to the plasma (Fig. 1). Several populations of endocytic vesicle deliver content membrane or TGN [3]. Recycling to the plasma membrane occurs to the early endosome from the plasma membrane. At least two via slow or fast pathways. “Fast” recycling takes material directly of these are generated by a clathrin-dependent pathway; APPL1- from an early endosome back to the plasma membrane, and is positive [1] and SNX15-positive [2] vesicles. The early endosome regulated by Rab4 and Rab35 [4,5]. In contrast, “slow” recycling transits through Rab11-positive recycling endosomes [6–8]. The ∗ Corresponding author. Tel.: +44 161 275 5646; fax: +44 161 275 5082. ∗∗ major pathways and important molecular components are shown Corresponding author. Tel.: +44 161 275 7846; fax: +44 161 275 5082. in Fig. 1. How each motor associates with various endocytic com- E-mail addresses: [email protected] (V. Allan), partments and contributes to endocytic function (detailed below) [email protected] (P. Woodman). 1 These authors contributed equally. is summarised in Table 1. http://dx.doi.org/10.1016/j.semcdb.2014.04.011 1084-9521/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). Please cite this article in press as: Granger E, et al. The role of the cytoskeleton and molecular motors in endosomal dynamics. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.04.011 G Model YSCDB-1564; No. of Pages 10 ARTICLE IN PRESS 2 E. Granger et al. / Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx Fig. 1. Overview of the endocytic pathway and the cytoskeleton. Transport steps are shown using solid arrows, maturation steps are shown using broken arrows. 2. Motor proteins and a minus end that is anchored in the microtubule organis- ing centre, normally located near the nucleus in non-dividing Microtubules support intracellular transport in a manner that cells. Microtubules support both short- and long-range move- is dependent on their intrinsic polarity. They possess a dynamic ments, using two types of motors: kinesins, with a few plus end that, in most cells, grows towards the periphery exceptions, move towards plus ends [9], whilst cytoplasmic Please cite this article in press as: Granger E, et al. The role of the cytoskeleton and molecular motors in endosomal dynamics. Semin Cell Dev Biol (2014), http://dx.doi.org/10.1016/j.semcdb.2014.04.011 G Model YSCDB-1564; No. of Pages 10 ARTICLE IN PRESS E. Granger et al. / Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx 3 Table 1 subunits (KIF3A paired with KIF3B or KIF3C) and an accessory sub- Motor proteins and endocytic trafficking. unit, KAP3. Other family members, such as KIF17, form homodimers Motor/subunit Organelle Adaptor molecule References [12,14]. The kinesin-3 family has many members, which may act as Kinesin-1 monomers or dimers. Other kinesins with roles in endosome move- ␤ EE Unknown [64,105] ment include the kinesin-13 KIF2 , and the minus-end-directed LE/lysosomes SKIP-Arl8 [64,111–113] KIFC1 and 2 (see Table 1). Kif5 Rab4/11 RE Gadkin-AP1 [134] Actin filaments also display polarity, with barbed and pointed EE tubules; SNX1 & Unknown [58] ends analogous to the plus and minus ends, respectively, of micro- 8 tubules, and generally support short-range movements in animal Kinesin-2 cells. The actin-based motors, myosins, share an evolutionarily con- Glut4 RE Rab4 [166] served core mechanism with kinesins [15], and also belong to a RE Rip11/FIP5 [133] Kif3A-Kif3B LE/lysosomes Unknown [65,109] superfamily [14]. Myosins walk to the barbed end of the filament, EE tubules; SNX4 Unknown [58] with the exception of myosin VI [9]. Those families most relevant to Kinesin-3 endocytic trafficking are myosins I, V and VI. Polarised actin poly- ␤ KIF1B LE/lysosomes Unknown [115,135] merisation on the surface of organelles to generate actin ‘comets’ KIF13A RE Rab11 [132] can also support organelle movement [16]. KIF16B EE/RE PtdIns-3P [107,109] Khc-73 (D. EE (Unknown) [106] melanogaster) 3. Uptake from the plasma membrane: the role of actin Kinesin-13 ␤ KIF2 LE/lysosomes Unknown [116] Uptake occurs through multiple routes, including clathrin- Kinesin-14 dependent endocytosis, caveolae, phagocytosis, macropinocytosis KIFC1 EE Unknown [67] and several other clathrin-independent pathways (reviewed in KIFC2 EE Unknown [66] [17]). Actin has a particularly well-characterised role during Dynein/dynactin phagocytosis (not a subject of this review, but see [18]) and LIC1 LE/lysosomes RILP [63] clathrin-dependent endocytosis [19]. In yeast, actin is absolutely LIC1/2 RE FIP3 [130,131] required for clathrin-dependent endocytosis unless the turgor LIC1 RE Rab4 [90] pressure across the plasma membrane is reduced experimen- LIC (D. rerio) LE/lysosomes JIP3 (in neurons) [100] tally [20]. In mammalian cells, actin is not always essential. Its IC LE/lysosomes Snapin [102] LC8 EE tubules; SNX4 Kibra [129] importance is more prominent when a larger force is required for Glued p150 LE/lysosomes RILP/ORP1L [96,97] budding, such as endocytosis at plasma membrane locations that Glued p150 EE tubules; SNX1/2 SNX5/6 [128] display a high degree of membrane rigidity [21], or during the p25 EE Hook [92–95] ingestion of larger cargoes [22]. Hence, actin has a clear role in Myosins generating force to assist uptake. Myosin 1e Coated pit Dynamin, [26] During endocytosis, actin polymerisation with the barbed ends synaptojanin pointing towards the membrane helps to stabilise and elongate the Myosin 1b EE Unknown [142–144] Myosin Va Endocytic vesicle Unknown [157] newly formed neck of a nascent vesicle by exerting force against Myosin Vb RE Rab11, Rab11-FIP2 [152,153] the membrane [19,23]. Type I myosins combine with verprolin Myosin Vb RE Hrs, CART [158] and WASP (Wiskott-Aldrich syndrome protein) family proteins to Myosin VI Coated vesicle DAB2 [32,33] activate the Arp2/3 complex, which in turn drives actin polymeri- Endocytic vesicle GIPC, Tom1 [35,39] sation [24,25]. These myosins are recruited to sites of endocytosis EE to RE LMTK2 [141] by elements of the endocytic machinery. For example, myosin 1e binds the scission protein dynamin and the phosphatidylinositol (PtdIns)-5 phosphatase synaptojanin-1 [26]. Since they can also dynein (henceforth called dynein) moves towards minus ends bind to membrane lipids whilst associated with actin filaments [10]. [27], type I myosins may also help to generate membrane tension Dynein is a large (1–2 MDa) motor complex (reviewed in [10]) and local membrane deformation [26,28]. Furthermore, myosin Ie that assembles around 2 copies of dynein heavy chain (DHC) [25] and actin polymerisation [23,29] may support the movement (Fig. 2A). DHC contains a motor domain, and a tail domain that binds of endocytic vesicles away from the plasma membrane. two copies each of intermediate chain (IC) and light-intermediate In mammalian cells the minus end-directed myosin VI is chain (LIC). IC in turn binds 3 types of light chain (LC; TCTEX, LC8 recruited to sites of clathrin-dependent endocytosis [30]. Con- and Roadblock/LC7). Two alternate genes encode each of these trasting with the function of type I myosins in modulating actin accessory subunits, and IC and LIC produce a range of differentially organisation and polymerisation, force generated by myosin VI spliced isoforms, so generating dynein complexes of considerable can directly contribute to vesicle formation, as demonstrated for heterogeneity.
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