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Myosin-Driven Intracellular Transport Downloaded from http://cshperspectives.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Myosin-Driven Intracellular Transport Margaret A. Titus Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455 Correspondence: [email protected] SUMMARY The delivery of intracellular material within cells is crucial for maintaining normal function. Myosins transport awide varietyof cargo, ranging from vesicles to ribonuclear protein particles (RNPs), in plants, fungi, and metazoa. The properties of a given myosin transporter are adapted to move on different actin filament tracks, either on the disordered actin networks at the cell cortex or along highly organized actin bundles to distribute their cargo in a localized manner or move it across long distances in the cell. Transport is controlled by selective recruitment of the myosin to its cargo that also plays a role in activation of the motor. Outline 1 Introduction 6 Movement along actin bundles 2 The transport myosins—Basic features 7 Long-distance transport 3 Intracellular transport of secretory and 8 Cytoplasmic streaming in plants endocytic vesicles 9 Conclusion 4 Diseases caused by defects in actin-based References organelle transport 5 RNA trafficking Editors: Thomas D. Pollard and Robert D. Goldman Additional Perspectives on The Cytoskeleton available at www.cshperspectives.org Copyright # 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a021972 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a021972 1 Downloaded from http://cshperspectives.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press M.A. Titus 1 INTRODUCTION yet well understood. It certainly requires that the appropri- ate motors are activated in the regions of the cell in which A remarkable feature of cells is the dynamic and often the microtubules and actin filaments overlap at the site of robust movement of their internal contents. Intracellular cargo transfer, and/or else already active motors might en- motility is used to position organelles where they are need- gage in atug-of-warand the greater poweror numberof one ed, such as targeting secretion to the apical regions of cells motor type might win over the other. It should be noted lining a lumen. The major cytoskeletal filament systems— that, in addition to translocation via motor-driven motility actin and microtubules—serve as the tracks for movement along filaments, actin polymerization can also power the of cellular cargo that is largely driven by their associated intracellular movement of vesicles, typically endocytic ves- cytoskeletal motors, kinesins, dynein, and myosins. Avari- icles, and even pathogenic bacteria, and that this occurs ety of cellularcontent is transported, including intracellular independently of microtubule motors. The focus of this vesicles such as endosomes and exosomes, organelles such review is on myosin-dependent movement of cargo along as melanosomes or mitochondria, and particles such as actin filaments. Selected examples will be presented to high- ribonucleoproteins (RNPs). In metazoan cells, transport light the diversity and shared features of motor-driven can be divided into two parts—long-distance movement transport along actin filaments in different cell types. along microtubules (reviewed by Barlan and Gelfand 2016) and relatively short-range transit along actin filaments. The 2 THE TRANSPORT MYOSINS—BASIC FEATURES polarized organization of the microtubule system, with many slow-growing ends embedded in the centrosome A variety of different myosins transport cargo within cells and the fast-growing ends extending all the way out to (reviewed by Sweeney and Holzbaur 2016). One key fea- the periphery, provides tracks for movement to the cellular ture of these motors is their distinctive carboxy-terminal periphery and back into the center of the cell. Although tail regions that bind to specific partner proteins to target these provide efficient highways for cargo, a local distribu- the myosin to a particular cellular location or organelle. tion system is needed, and that is provided by the actin Another property of transporters is their ability to move cytoskeleton. continuously along actin filaments, typically on dimeriza- The cytoskeletal actin network is generally not polar- tion or multimerization. The myosin V family of myosins ized and, instead, filaments are randomly oriented in the (reviewed in Hammer and Sellers 2011) are among the cell, allowing for the movement of cargo all throughout the most widely used motors for actin-based transport and region in which filaments are found (for review, see Svitki- they are found in a diverse set of organisms ranging na 2016). However, there are select regions of the cell in from amoebae to yeast to human, suggesting that they which actin is arranged in a more orderly manner. The are among the most ancient of actin-dependent translo- actin filaments in cortical regions immediately beneath cators. Myosin Vs have roles in the actin-based motility of the plasma membrane are generally arranged with their organelles, vesicles, and RNPs, and a wide range of studies barbed (or fast-growing) ends oriented toward the plasma of the intracellular transport of these cargos have revealed membrane, providing a path for myosin-dependent move- several fundamental aspects of myosin-dependent move- ment of cargo either to or from the plasma membrane, ment along actin within a cell. based on the directionality of the associated motor. Spe- All known myosins with the exception of one, myosin cialized protrusive structures comprising parallel bundles VI, move in the same direction on the actin filament— of actin with their barbed ends at the membrane and point- toward the barbed end. Given that actin filaments within ed ends at the base, such as filopodia, stereocilia, and mi- the cell are generally organized in a random fashion, the crovilli, also serve as cellular “superhighways” for cargo that barbed end motors are all perfectly well-suited for distrib- is targeted for delivery within these structures, anchored at uting cargo throughout a network of filaments. However, their tip or targeted for secretion. in those regions of the cell in which actin filaments have a The ability of cargo to move along either filament sys- defined orientation, such as at the periphery where they are tem means that intracellular transport is coordinated in a oriented with their barbed ends toward the membrane, general sense. Intracellular vesicles or organelles have been barbed end–directed myosins, such as myosin V, will shown to move along one filament system and then switch move cargo toward the plasma membrane, whereas the over to the other (for examples, see Rodionov et al. 1998; pointed end–directed myosin VI would work in opposi- Rogers and Gelfand, 1998; Schuster et al. 2011; Schroeder tion to transport vesicles away from the plasma membrane et al. 2012). The mechanism by which an organelle can and into the interior of the cell. The same would be true for move along one filament type and then switch to another the movement of myosins along the parallel actin bundles or change directionality when moving on a filament is not found in filopodia, microvilli, and stereocilia. 2 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a021972 Downloaded from http://cshperspectives.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Myosin Transport The actin filaments themselves can also have an impact et al. 2011). Another mechanism for activating myosins + on translocation. For example, myosin Ic plays a role in the could be through Ca2 binding to calmodulin light chains transport of vesicles containing GLUT4 in adipocytes, but bound to the lever arm region that unfolds the myosin (see it is unable to bind to actin filaments with the tropomyosin below). Tpm3.1 bound. Thus, this myosin tends to selectively drive Transport by myosins can also be activated, or signifi- cargo transport along filaments without tropomyosin (Kee cantly enhanced, by converting a monomer to a dimer by et al. 2015). Regulating the levels of Tpm3.1 in the cortex its binding partner(s), enabling the motor to move proc- might provide the cell with a mechanism to control the essively along actin. Cytosolic myosin VI is a monomer; transit of GLUT4 vesicles in that region. The nucleotide however, binding of its partners optineurin or Dab2 to state of an actin filament can also play a role in regulating the tail dimerizes the motor, which is then able to move myosin movement. Myosin Va takes more steps on a grow- long distances along actin (Phichith et al. 2009; Yu et al. ing actin filament (the actin monomer has ADP.Pi bound) 2009). Similarly, myosin VIIA is a monomer and, when than on older filaments (ADP actin) (Zimmermann et al. expressed in COS7 cells, it is largely cytosolic. Coexpression 2015). In contrast, myosin VI prefers “older” ADP actin with its binding partner MyRIP dimerizes the motor, filaments. These differences in run length correlate with which can then translocate along actin filaments of a filo- the directionality of each motor and could play a role in podium to the tip (Sakai et al. 2011). favoring the movement of one motor or another in regions Another mode of modulating transport is through the of the cell with more stable, older filament networks versus ability of myosins to sense and respond to forces. High load regions in which the actin filaments turn over rapidly. can significantly slow the mechanochemical cycles of some The activity of transport myosins is tightly regulated to myosins, converting them to an anchor. For example, just prevent the cargo-attached motor from interacting with 1 picoNewton (pN) of force significantly slows ADP release actin filaments until it is at the correct location and to avoid from myosin Ib, increasing the time it remains bound to unproductive interactions with actin filaments when the actin (Laakso et al.
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