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Microtubule-Based Transport and the Distribution, Tethering, and Organization of Organelles

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Microtubule-Based Transport and the Distribution, Tethering, and Organization of Organelles Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Microtubule-Based Transport and the Distribution, Tethering, and Organization of Organelles Kari Barlan1 and Vladimir I. Gelfand2 1Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois 60637 2Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611 Correspondence: [email protected] SUMMARY Microtubules provide long tracks along which a broad range of organelles and vesicles are transported by kinesin and dynein motors. Motor protein complexes also tether cargoes to cytoskeletal filaments, helping facilitate their interaction and communication. The generation of biochemically distinct microtubule subpopulations allows subsets of motors to recognize a given microtubule identity, allowing further organization within the cytoplasm. Both transport and tethering are spatiotemporally regulated through multiple modes, including acute mod- ification of both motor–cargo and motor–track associations by various physiological signals. Strict regulation of intracellular transport is particularly important in specialized cell types such as neurons. Here, we review general mechanisms by which cargo transport is controlled and also highlight examples of transport regulated by multiple mechanisms. Outline 1 Introduction 4 Conclusion 2 Fundamentals of microtubule-based References transport 3 Examples of regulated transport Editors: Thomas D. Pollard and Robert D. Goldman Additional Perspectives on The Cytoskeleton available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a025817 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a025817 1 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press K. Barlan and V.I. Gelfand 1 INTRODUCTION brane organelles, messenger RNA (mRNA) transcripts, protein complexes, and viruses, among others. In compar- The ability of a cell to respond and adapt to changing phys- ison with this diversity, only a small numberof components iological cues relies on continual reorganization of the make up the intracellular transport machinery—three fam- contents of its cytoplasm. This is accomplished primarily ilies of motors and two types of tracks (Fig. 1). Remarkably, through active transport along cytoskeletal filaments by this handful of building blocks can be combined and molecular motor proteins. The collection of cargoes present adapted to create a myriad of finely tuned machines capa- in any given cell is vast and extremely varied—diverse mem- ble of transporting a full range of cellular cargoes. A C Dynein Myosin Kinesin Growth cone B Cell body D Axon Figure 1. Membrane organelles require multiple motors and cytoskeletal filaments for their distribution. (A)Ina steady-state eukaryotic cell, the molecular motors kinesin and dynein transport cargo over long distances along radially arranged microtubules (purple). Actin filaments (dark yellow) are denser near the cell periphery and primarily support short-range transport events by myosin motors. (B) The architecture of the cytoskeletal transport machinery in a neuron is somewhat analogous, with bundles of microtubules (purple tracks) extending from the cell body into the axon and dendrites (not highlighted in this figure), and with actin concentrated in the growth cone at the axon terminal. (C) Organelles are often moved by multiple motors, including motors of opposite polarity and on different cytoskeletal tracks. (D) Microtubules and actin also provide scaffolding where organelle interactions can take place, as attachment to a filament restricts three-dimensional diffusion of organelles to movement in one dimension. The activity of these motors, and the way in which individual cargoes are transported, is likely regulated by molecular factors specific to individual organelles to allow for rapid changes in distribution and motility. (Modified from Barlan et al. 2013b.) Note that the various motors, cargoes, and cellular constituents are not illustrated here to scale. 2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a025817 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Transport and Tethering on Microtubules Molecular motors have two important, interdependent function and synaptic activity must be transported along functions in intracellular transport. Their primary func- microtubules from the cell body, where the cargoes are tion is to deliver cargoes to discrete cellular locations in synthesized, toward axonal synapses that can be many cen- response to various physiological stimuli. But motors timeters away. The cytoskeletal architecture of the neuron is also play a direct role in facilitating molecular exchanges analogous to that of other cells (Fig. 1). Bundled microtu- and chemical interactions between membrane organelles. bules extend along the axon shaft, with their plus ends By tethering organelles to a cytoskeletal track, motors act toward the axon terminal, and actin filaments are enriched to limit three-dimensional diffusion to movement in one in the growth cone, a structure near the distal tip of the dimension and thus influence when and where particu- axon, and at the synapses. lar intermolecular associations occur and increase the effi- Understanding how molecular motors function in ax- ciency of component exchange between individual cellular onal transport is key to our understanding of a range of compartments. neurological diseases (Chevalier-Larsen and Holzbaur Here, we focus on the various ways in which the micro- 2006; Hirokawa et al. 2010). Mutations in the most crucial tubule cytoskeleton supports the delivery and distribution components of axonal transport are typically not found of cargoes and the types of physiological stimuli that con- in diseases as they are generally lethal. However, various trol these events. Examples highlighting the acute regula- models of neurological disease have lent themselves to tion of transport in space and time will also be discussed. the study of axonal transport regulation and have led to the discovery of important accessory proteins (Bowman et al. 2000; Smith et al. 2000; Stowers et al. 2002; Gindhart 2 FUNDAMENTALS OF MICROTUBULE-BASED et al. 2003). Because of the high physiological significance TRANSPORT and unique polarized architecture, the neuron has become 2.1 Motor Proteins Power Cargo Transport along a popular and powerful model for investigating microtu- Cytoskeletal Filaments bule-based transport. Microtubules and actin filaments together make up the Another model system used to study cargo transport tracks along which cargoes can be transported, delivered, comes from the color-changing cells of amphibians and and anchored (Fig. 1). As such, they are key components fish. These animals use the regulated transport of pig- crucial to organizing the rest of the cytoplasm in a cell. The ment-containing organelles, called melanosomes, as a arrangement of each filament network is best suited for a means for rapid color change. This behavior is often in- distinct kind of transport. These networks complement duced by changes in the animal’s environment. Although one another to provide the architecture necessary to sustain melanosomes constantly undergo indiscriminate short- both directed transport events and organelle tethering. range movements, their motility becomes highly per- Microtubules are long polymers that are polarized both sistent and synchronous in response to hormonal signals. in their intrinsic structure and also, usually, in their ar- This results in a dramatic reorganization of pigment within rangement in the cell. Typically their fast-growing plus each individual cell and the lightening or darkening of the ends extend toward the cell periphery, whereas their minus animal’s skin or scales. Details of the regulation of mela- ends are located closer to the cell center and are often nosome transport will be discussed below. anchored at the centrosome, near the nucleus. This well- The cytoskeletal transport system can also be seized organized, radial arrangement of filaments provides tracks by viruses to aid in their replication and spread. Vaccinia for fast transport of cargoes by members of two classes virus, for example, replicates its genome and assembles of molecular motor proteins (see Sweeney and Holzbaur viral particles in the cytoplasm of cells, and then it uses 2016). Dynein motors move toward the minus ends of kinesin-dependent transport to shuttle these viral particles microtubules, whereas most kinesins move toward the to the plasma membrane for release from the cell (Leite plus ends. In contrast to microtubules, actin filaments are and Way 2015). The timing of viral particle association shorter and, although the filaments themselves are polar- with kinesin is regulated, in part, by the timing of viral ized, they typically form a more randomly oriented mesh- gene expression to ensure that only mature viral particles work that is most dense near the cell cortex (see Svitkina are transported to the cell periphery. We will discuss an 2016). Myosin motors move along actin filaments and pri- example of viral particle transport below. marily contribute to localized, short-range movements of Each episode of cargo transport requires three distinct cargoes.
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