Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Selective motor activation in organelle transport along axons

Nature Reviews Molecular Cell Biology volume 23, pages 699–714 (2022)Cite this article

Subjects

Abstract

The active transport of organelles and other cargos along the axon is required to maintain neuronal health and function, but we are just beginning to understand the complex regulatory mechanisms involved. The molecular motors, cytoplasmic dynein and kinesins, transport cargos along microtubules; this transport is tightly regulated by adaptors and effectors. Here we review our current understanding of motor regulation in axonal transport. We discuss the mechanisms by which regulatory proteins induce or repress the activity of dynein or kinesin motors, and explore how this regulation plays out during organelle trafficking in the axon, where motor activity is both cargo specific and dependent on subaxonal location. We survey several well-characterized examples of membranous organelles subject to axonal transport — including autophagosomes, endolysosomes, signalling endosomes, mitochondria and synaptic vesicle precursors — and highlight the specific mechanisms that regulate motor activity to provide localized trafficking within the neuron. Defects in axonal transport have been implicated in conditions ranging from developmental defects in the brain to neurodegenerative disease. Better understanding of the underlying mechanisms will be essential to develop more-effective treatment options.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Microtubule and motor organization in neurons.
Fig. 2: Motor autoinhibition and activation.
Fig. 3: Models of intermotor coordination.
Fig. 4: Many motor effectors induce both anterograde and retrograde transport.
Fig. 5: Axonal transport of mitochondria, endolysosomes, and synaptic components.
Fig. 6: Axonal transport of autophagic vacuoles and signalling endosomes.

Similar content being viewed by others

References

  1. Ramón y Cajal, S. Textura del Sistema Nervioso del Hombre y de los Vertebrados (Texture of the Nervous System of Man and the Vertebrates) (Springer, 1899).

  2. Koltun, B. et al. Measuring mRNA translation in neuronal processes and somata by tRNA-FRET. Nucleic Acids Res. 48, e32 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Misgeld, T. & Schwarz, T. L. Mitostasis in neurons: maintaining mitochondria in an extended cellular architecture. Neuron 96, 651–666 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Farfel-Becker, T. et al. Neuronal soma-derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity. Cell Rep. 28, 51–64.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Guillaud, L., El-Agamy, S. E., Otsuki, M. & Terenzio, M. Anterograde axonal transport in neuronal homeostasis and disease. Front. Mol. Neurosci. 13, 556175 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kulkarni, A., Chen, J. & Maday, S. Neuronal autophagy and intercellular regulation of homeostasis in the brain. Curr. Opin. Neurobiol. 51, 29–36 (2018).

    Article  CAS  PubMed  Google Scholar 

  7. Cosker, K. E. & Segal, R. A. Neuronal signaling through endocytosis. Cold Spring Harb. Perspect. Biol. 6, a020669 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Vale, R. D. Intracellular transport using microtubule-based motors. Ann. Rev. Cell Bioi 3, 347–378 (1987).

    Article  CAS  Google Scholar 

  9. Heidemann, S. R., Landers, J. M. & Hamborg, M. A. Polarity orientation of axonal microtubules. J. Cell Biol. 91, 661–665 (1981).

    Article  CAS  PubMed  Google Scholar 

  10. Baas, P. W., Deitch, J. S., Black, M. M. & Banker, G. A. Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Proc. Natl Acad. Sci. USA 85, 8335–8339 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tas, R. P. et al. Differentiation between oppositely oriented microtubules controls polarized neuronal transport. Neuron 96, 1264–1271.e5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schroer, T. A., Steuer, E. R. & Sheetz, M. P. Cytoplasmic dynein is a minus end-directed motor for membranous organelles. Cell 56, 937–946 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Schnapp, B. J. & Reese, T. S. Dynein is the motor for retrograde axonal transport of organelles. Proc. Natl Acad. Sci. USA 86, 1548–1552 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vale, R. D., Reese, T. S. & Sheetz, M. P. Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility. Cell 42, 39–50 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vale, R. D. et al. Different axoplasmic proteins generate movement in opposite directions along microtubules in vitro. Cell 43, 623–632 (1985).

    Article  CAS  PubMed  Google Scholar 

  16. Roy, S. Finding order in slow axonal transport. Curr. Opin. Neurobiol. 63, 87–94 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hendricks, A. G. et al. Motor coordination via a tug-of-war mechanism drives bidirectional vesicle transport. Curr. Biol. 20, 697–702 (2010). Using subcellular fractionation, in vitro reconstitution and quantitative photobleaching, this study demonstrates the co-purification of oppositely directed cytoplasmic dynein and kinesin motors on isolated late endosomes/lysosomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Maday, S., Wallace, K. E. & Holzbaur, E. L. F. Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons. J. Cell Biol. 196, 407–417 (2012). Live imaging of organelle dynamics and subcellular fractionation of autophagosomes from mouse brain demonstrate that the tightly regulated motility of associated dynein and kinesin motors leads to the processive motility of autophagosomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hancock, W. O. Bidirectional cargo transport: moving beyond tug of war. Nat. Rev. Mol. Cell Biol. 15, 615–628 (2014). This authoritative review covers the conceptual framework and experimental support for models of bidirectional transport of organelles along microtubules.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hirokawa, N., Niwa, S. & Tanaka, Y. Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron 68, 610–638 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Chen, X.-J., Xu, H., Cooper, H. M. & Liu, Y. Cytoplasmic dynein: a key player in neurodegenerative and neurodevelopmental diseases. Sci. China Life Sci. 57, 372–377 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Miki, H., Setou, M., Kaneshiro, K. & Hirokawa, N. All kinesin superfamily protein, KIF, genes in mouse and human. Proc. Natl Acad. Sci. USA 98, 7004–7011 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hunter, B. & Allingham, J. S. These motors were made for walking. Protein Sci. 29, 1707–1723 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gumy, L. F. et al. The kinesin-2 family member KIF3C regulates microtubule dynamics and is required for axon growth and regeneration. J. Neurosci. 33, 11329–11345 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Farkhondeh, A., Niwa, S., Takei, Y. & Hirokawa, N. Characterizing KIF16B in neurons reveals a novel intramolecular “stalk inhibition” mechanism that regulates its capacity to potentiate the selective somatodendritic localization of early endosomes. J. Neurosci. 35, 5067–5086 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lipka, J., Kapitein, L. C., Jaworski, J. & Hoogenraad, C. C. Microtubule-binding protein doublecortin-like kinase 1 (DCLK1) guides kinesin-3-mediated cargo transport to dendrites. EMBO J. 35, 302–318 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ghiretti, A. E. et al. Activity-dependent regulation of distinct transport and cytoskeletal remodeling functions of the dendritic kinesin KIF21B. Neuron 92, 857–872 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Masucci, E. M., Relich, P. K., Lakadamyali, M., Ostap, E. M. & Holzbaur, E. L. F. Microtubule dynamics influence the retrograde biased motility of kinesin-4 motor teams in neuronal dendrites. Mol. Biol. Cell. https://doi.org/10.1091/mbc.E21-10-0480 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Franker, M. A. et al. Three-step model for polarized sorting of KIF17 into dendrites. Curr. Biol. 26, 1705–1712 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Fukuda, Y. et al. Binding and transport of SFPQ-RNA granules by KIF5A/KLC1 motors promotes axon survival. J. Cell Biol. 220, e202005051 (2020).

    Article  PubMed Central  Google Scholar 

  31. Hummel, J. J. A. & Hoogenraad, C. C. Specific KIF1A–adaptor interactions control selective cargo recognition. J. Cell Biol. 220, e202105011 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cai, Q., Pan, P.-Y. & Sheng, Z.-H. Syntabulin–kinesin-1 family member 5B-mediated axonal transport contributes to activity-dependent presynaptic assembly. J. Neurosci. 27, 7284–7296 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yang, R. et al. A novel strategy to visualize vesicle-bound kinesins reveals the diversity of kinesin-mediated transport. Traffic 20, 851–866 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hirokawa, N., Noda, Y., Tanaka, Y. & Niwa, S. Kinesin superfamily motor proteins and intracellular transport. Nat. Rev. Mol. Cell Biol. 10, 682–696 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Nabb, A. T., Frank, M. & Bentley, M. Smart motors and cargo steering drive kinesin-mediated selective transport. Mol. Cell. Neurosci. 103, 103464 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kaan, H. Y. K., Hackney, D. D. & Kozielski, F. The structure of the kinesin-1 motor-tail complex reveals the mechanism of autoinhibition. Science 333, 883–885 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Qin, J., Zhang, H., Geng, Y. & Ji, Q. How kinesin-1 utilize the energy of nucleotide: the conformational changes and mechanochemical coupling in the unidirectional motion of kinesin-1. Int. J. Mol. Sci. 21, 6977 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  38. Ren, J. et al. Coiled-coil 1-mediated fastening of the neck and motor domains for kinesin-3 autoinhibition. Proc. Natl Acad. Sci. USA 115, E11933–E11942 (2018). This careful structural study uncovers the mechanism by which kinesin 3 is autoinhibited in vitro.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Endow, S. A., Kull, F. J. & Liu, H. Kinesins at a glance. J. Cell Sci. 123, 3420–3424 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Olenick, M. A. & Holzbaur, E. L. F. Dynein activators and adaptors at a glance. J. Cell Sci. 132, jcs227132 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Reck-Peterson, S. L., Redwine, W. B., Vale, R. D. & Carter, A. P. The cytoplasmic dynein transport machinery and its many cargoes. Nat. Rev. Mol. Cell Biol. https://doi.org/10.1038/s41580-018-0004-3 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Vallee, R. B., McKenney, R. J. & Ori-McKenney, K. M. Multiple modes of cytoplasmic dynein regulation. Nat. Cell Biol. 14, 224–230 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Canty, J. T. & Yildiz, A. Activation and regulation of cytoplasmic dynein. Trends Biochem. Sci. 45, 440–453 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Waterman-Storer, C. M. et al. The interaction between cytoplasmic dynein and dynactin is required for fast axonal transport. Proc. Natl Acad. Sci. USA 94, 12180–12185 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. McKenney, R. J., Huynh, W., Tanenbaum, M. E., Bhabha, G. & Vale, R. D. Activation of cytoplasmic dynein motility by dynactin-cargo adapter complexes. Science 345, 337–341 (2014). This influential study demonstrates the potent activation of dynein motility through the assembly of an active co-complex of the motor with dynactin and an activating adaptor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dutta, M. & Jana, B. Computational modeling of dynein motor proteins at work. Chem. Commun. 57, 272–283 (2021).

    Article  CAS  Google Scholar 

  47. Zhang, K. et al. Cryo-EM reveals how human cytoplasmic dynein is auto-inhibited and activated. Cell 169, 1303–1314.e18 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cai, D., Hoppe, A. D., Swanson, J. A. & Verhey, K. J. Kinesin-1 structural organization and conformational changes revealed by FRET stoichiometry in live cells. J. Cell Biol. 176, 51–63 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yip, Y. Y. et al. The light chains of kinesin-1 are autoinhibited. Proc. Natl Acad. Sci. USA 113, 2418–2423 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lee, I.-G. et al. A conserved interaction of the dynein light intermediate chain with dynein-dynactin effectors necessary for processivity. Nat. Commun. 9, 986 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Celestino, R. et al. A transient helix in the disordered region of dynein light intermediate chain links the motor to structurally diverse adaptors for cargo transport. PLoS Biol. 17, e3000100 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Cockburn, J. J. B. et al. Insights into kinesin-1 activation from the crystal structure of KLC2 bound to JIP3. Structure 26, 1486–1498.e6 (2018). The authors of this stuy solved the structure of the KLC tetricopeptide repeat domain bound to JIP3, providing structural insight into kinesin 1 activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sanger, A. et al. SKIP controls lysosome positioning using a composite kinesin-1 heavy and light chain-binding domain. J. Cell Sci. 130, 1637–1651 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Bruyère, J. et al. Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of huntingtin. eLife 9, e56371 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Colin, E. et al. Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J. 27, 2124–2134 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Scaramuzzino, C., Cuoc, E. C., Pla, P., Humbert, S. & Saudou, F. Calcineurin and huntingtin form a calcium-sensing machinery that directs neurotrophic signals to the nucleus. Sci. Adv. 8, eabj8812 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Fu, M. & Holzbaur, E. L. F. JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors. J. Cell Biol. 202, 495–508 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Boecker, C. A., Goldsmith, J., Dou, D., Cajka, G. G. & Holzbaur, E. L. F. Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes. Curr. Biol. https://doi.org/10.1016/j.cub.2021.02.061 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Steger, M. et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife 5, e12813 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Waschbüsch, D. et al. Structural basis for rab8a recruitment of RILPL2 via LRRK2 phosphorylation of switch 2. Structure 28, 406–417.e6 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Nirschl, J. J., Magiera, M. M., Lazarus, J. E., Janke, C. & Holzbaur, E. L. F. α-Tubulin tyrosination and CLIP-170 phosphorylation regulate the initiation of dynein-driven transport in neurons. Cell Rep. 14, 2637–2652 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Monroy, B. Y. et al. A combinatorial MAP code dictates polarized microtubule transport. Dev. Cell 53, 60–72.e4 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Roll-Mecak, A. The tubulin code in microtubule dynamics and information encoding. Dev. Cell 54, 7–20 (2020).

    Article  CAS  PubMed  Google Scholar 

  64. Janke, C. & Magiera, M. M. The tubulin code and its role in controlling microtubule properties and functions. Nat. Rev. Mol. Cell Biol. 21, 307–326 (2020).

    Article  CAS  PubMed  Google Scholar 

  65. Sun, T. et al. JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport by activating kinesin-1. Cell. Mol. Life Sci. 74, 4027–4044 (2017).

    Article  CAS  PubMed  Google Scholar 

  66. Sun, F., Zhu, C., Dixit, R. & Cavalli, V. Sunday Driver/JIP3 binds kinesin heavy chain directly and enhances its motility. EMBO J. 30, 3416–3429 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Niwa, S. et al. Autoinhibition of a neuronal kinesin UNC-104/KIF1A regulates the size and density of synapses. Cell Rep. 16, 2129–2141 (2016). This influential work illustrates the importance of autoinhibition for proper localization of axonal cargo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kendrick, A. A. et al. Hook3 is a scaffold for the opposite-polarity microtubule-based motors cytoplasmic dynein-1 and KIF1C. J. Cell Biol. 218, 2982–3001 (2019). This important study uses single-molecule motility assays to show the motor effector HOOK3 activates both kinesin and dynein and forms co-complexes with both motors simultaneously.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kevenaar, J. T. et al. Kinesin-binding protein controls microtubule dynamics and cargo trafficking by regulating kinesin motor activity. Curr. Biol. 26, 849–861 (2016).

    Article  CAS  PubMed  Google Scholar 

  70. Atherton, J. et al. The mechanism of kinesin inhibition by kinesin-binding protein. eLife 9, e61481 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Keren-Kaplan, T. & Bonifacino, J. S. ARL8 relieves SKIP autoinhibition to enable coupling of lysosomes to kinesin-1. Curr. Biol. 31, 540–554.e5 (2021).

    Article  CAS  PubMed  Google Scholar 

  72. Vilela, F. et al. Structural characterization of the RH1-LZI tandem of JIP3/4 highlights RH1 domains as a cytoskeletal motor-binding motif. Sci. Rep. 9, 1–15 (2019).

    Article  CAS  Google Scholar 

  73. Guardia, C. M., Farías, G. G., Jia, R., Pu, J. & Bonifacino, J. S. BORC functions upstream of kinesins 1 and 3 to coordinate regional movement of lysosomes along different microtubule tracks. Cell Rep. 17, 1950–1961 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. De Pace, R. et al. Synaptic vesicle precursors and lysosomes are transported by different mechanisms in the axon of mammalian neurons. Cell Rep. 31, 107775 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Montagnac, G. et al. ARF6 Interacts with JIP4 to control a motor switch mechanism regulating endosome traffic in cytokinesis. Curr. Biol. 19, 184–195 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Lund, V. K. et al. Rab2 drives axonal transport of dense core vesicles and lysosomal organelles. Cell Rep. 35, 108973 (2021).

    Article  CAS  PubMed  Google Scholar 

  77. Jongsma, M. L. et al. SKIP-HOPS recruits TBC1D15 for a Rab7-to-Arl8b identity switch to control late endosome transport. EMBO J. 39, e102301 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Niwa, S. et al. BORC regulates the axonal transport of synaptic vesicle precursors by activating ARL-8. Curr. Biol. 27, 2569–2578.e4 (2017). This important C. elegans study illustrates how BORC functions upstream, specifically as a GEF, of ARL-8 to indirectly recruit and activate kinesin on axonal cargo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Niwa, S., Tanaka, Y. & Hirokawa, N. KIF1Bβ- and KIF1A-mediated axonal transport of presynaptic regulator Rab3 occurs in a GTP-dependent manner through DENN/MADD. Nat. Cell Biol. 10, 1269–1279 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Marzo, M. G., Griswold, J. M. & Markus, S. M. Pac1/LIS1 stabilizes an uninhibited conformation of dynein to coordinate its localization and activity. Nat. Cell Biol. 22, 559–569 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Elshenawy, M. M. et al. Lis1 activates dynein motility by modulating its pairing with dynactin. Nat. Cell Biol. 22, 570–578 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Htet, Z. M. et al. LIS1 promotes the formation of activated cytoplasmic dynein-1 complexes. Nat. Cell Biol. 22, 518–525 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Feng, Q., Gicking, A. M. & Hancock, W. O. Dynactin p150 promotes processive motility of DDB complexes by minimizing diffusional behavior of dynein. Mol. Biol. Cell. 31, 782–792 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Olenick, M. A., Tokito, M., Boczkowska, M., Dominguez, R. & Holzbaur, E. L. F. Hook adaptors induce unidirectional processive motility by enhancing the dynein-dynactin interaction. J. Biol. Chem. 291, 18239–18251 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Urnavicius, L. et al. Cryo-EM shows how dynactin recruits two dyneins for faster movement. Nature 554, 202–206 (2018). This influential study uses electron microscopy and single-molecule motility assays to reveal that dynein-activating adaptors can recruit an additional dynein complex to induce greater force production and velocity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Elshenawy, M. M. et al. Cargo adaptors regulate stepping and force generation of mammalian dynein–dynactin. Nat. Chem. Biol. 15, 1093–1101 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lee, I.-G., Cason, S. E., Alqassim, S. S., Holzbaur, E. L. F. & Dominguez, R. A tunable LIC1-adaptor interaction modulates dynein activity in a cargo-specific manner. Nat. Commun. 11, 5695 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gama, J. B. et al. Molecular mechanism of dynein recruitment to kinetochores by the Rod–Zw10–Zwilch complex and Spindly. J. Cell Biol. 216, 943–960 (2017). This study identifies the two canonical motifs present in many dynein-activating adaptors: CC1 and Spindly motifs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Schroeder, C. M. & Vale, R. D. Assembly and activation of dynein–dynactin by the cargo adaptor protein Hook3. J. Cell Biol. 214, 309–318 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cason, S. E. et al. Sequential dynein effectors regulate axonal autophagosome motility in a maturation-dependent pathway. J. Cell Biol. 220, e202010179 (2021). This careful study uses both live imaging and in vitro reconstitution to elucidate a sequential pathway involving multiple activating adaptors for dynein that regulates autophagosome trafficking along the axon.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sladewski, T. E. et al. Recruitment of two dyneins to an mRNA-dependent Bicaudal D transport complex. eLife 7, e36306 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Grotjahn, D. A. et al. Cryo-electron tomography reveals that dynactin recruits a team of dyneins for processive motility. Nat. Struct. Mol. Biol. 25, 203–207 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ohashi, K. G. et al. Load-dependent detachment kinetics plays a key role in bidirectional cargo transport by kinesin and dynein. Traffic 20, 284–294 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Monzon, G. A. et al. Stable tug-of-war between kinesin-1 and cytoplasmic dynein upon different ATP and roadblock concentrations. J. Cell Sci. 133, jcs249938 (2020).

    Article  CAS  PubMed  Google Scholar 

  95. Rai, A. K., Rai, A., Ramaiya, A. J., Jha, R. & Mallik, R. Molecular adaptations allow dynein to generate large collective forces inside cells. Cell 152, 172–182 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Rai, A. et al. Dynein clusters into lipid microdomains on phagosomes to drive rapid transport toward lysosomes. Cell 164, 722–734 (2016). The authors establish a model of the regulation of cytoplasmic dynein motor activity by clustering on organelle cargo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hou, W. et al. Dynamic dissection of dynein and kinesin-1 cooperatively mediated intercellular transport of porcine epidemic diarrhea coronavirus along microtubule using single virus tracking. Virulence 12, 615–629 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Fenton, A. R., Jongens, T. A. & Holzbaur, E. L. F. Mitochondrial adaptor TRAK2 activates and functionally links opposing kinesin and dynein motors. Nat. Commun. 12, 4578 (2021). This in vitro study demonstrates that the mitochondrial adaptor protein TRAK2 activates both dynein and kinesin motors, and functionally integrates the activities of these opposing motors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Martin, M. et al. Cytoplasmic dynein, the dynactin complex, and kinesin are interdependent and essential for fast axonal transport. Mol. Biol. Cell. 10, 3717–3728 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Twelvetrees, A. E., Lesept, F., Holzbaur, E. L. F. & Kittler, J. T. The adaptor proteins HAP1a and GRIP1 collaborate to activate the kinesin-1 isoform KIF5C. J. Cell Sci. 132, jcs215822 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Quintanilla, R. A., Tapia-Monsalves, C., Vergara, E. H., Pérez, M. J. & Aranguiz, A. Truncated tau induces mitochondrial transport failure through the impairment of TRAK2 protein and bioenergetics decline in neuronal cells. Front. Cell. Neurosci. 14, 175 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhao, Y. et al. Metaxins are core components of mitochondrial transport adaptor complexes. Nat. Commun. 12, 83 (2021). This interesting C. elegans article identifies two new players in mitochondrial motility, MTX1 and MTX2, that coordinate bidirectional motility through contacts with Miro, TRAK1/2 and KLC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. López-Doménech, G. et al. Miro proteins coordinate microtubule- and actin-dependent mitochondrial transport and distribution. EMBO J. 37, 321–336 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  104. van Spronsen, M. et al. TRAK/Milton motor-adaptor proteins steer mitochondrial trafficking to axons and dendrites. Neuron 77, 485–502 (2013).

    Article  PubMed  Google Scholar 

  105. Henrichs, V. et al. Mitochondria-adaptor TRAK1 promotes kinesin-1 driven transport in crowded environments. Nat. Commun. 11, 3123 (2020). This is a striking demonstration of the activation of kinesin 1 by the mitochondrially associated scaffolding protein TRAK1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Canty, J. T., Hensley, A. & Yildiz, A. TRAK adaptors coordinate the recruitment and activation of dynein and kinesin to control mitochondrial transport. Preprint at bioRxiv https://doi.org/10.1101/2021.07.30.454553 (2021).

    Article  Google Scholar 

  107. Kang, J.-S. et al. Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell 132, 137–148 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Gutnick, A., Banghart, M. R., West, E. R. & Schwarz, T. L. The light-sensitive dimerizer zapalog reveals distinct modes of immobilization for axonal mitochondria. Nat. Cell Biol. 21, 768–777 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Basu, H. et al. FHL2 anchors mitochondria to actin and adapts mitochondrial dynamics to glucose supply. J. Cell Biol. 220, e201912077 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Eberhardt, E. L., Ludlam, A. V., Tan, Z. & Cianfrocco, M. A. Miro: a molecular switch at the center of mitochondrial regulation. Protein Sci. 29, 1269–1284 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Cioni, J.-M. et al. Late endosomes act as mRNA translation platforms and sustain mitochondria in axons. Cell 176, 56–72.e15 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Guo, X., Farías, G. G., Mattera, R. & Bonifacino, J. S. Rab5 and its effector FHF contribute to neuronal polarity through dynein-dependent retrieval of somatodendritic proteins from the axon. Proc. Natl Acad. Sci. USA 113, E5318–E5327 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Johnson, D. E., Ostrowski, P., Jaumouillé, V. & Grinstein, S. The position of lysosomes within the cell determines their luminal pH. J. Cell Biol. 212, 677–692 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kulkarni, V. V. & Maday, S. Neuronal endosomes to lysosomes: a journey to the soma. J. Cell Biol. 217, 2977–2979 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hoepfner, S. et al. Modulation of receptor recycling and degradation by the endosomal kinesin KIF16B. Cell 121, 437–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Olenick, M. A., Dominguez, R. & Holzbaur, E. L. F. Dynein activator Hook1 is required for trafficking of BDNF-signaling endosomes in neurons. J. Cell Biol. 218, 220–233 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Villari, G. et al. Distinct retrograde microtubule motor sets drive early and late endosome transport. EMBO J. 39, e103661 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Christensen, J. R. et al. Cytoplasmic dynein-1 cargo diversity is mediated by the combinatorial assembly of FTS-Hook-FHIP complexes. eLife 10, e74538 (2021). Proximity biotinylation and follow-up cell culture and motility assays are used to determine the complex assemblies and relevant cargos of the dynein activators HOOK1, HOOK2 and HOOK3 and their interactors FHIP1A, FHIP1B, FHIP2A and FHIP2B.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Siddiqui, N. et al. PTPN21 and Hook3 relieve KIF1C autoinhibition and activate intracellular transport. Nat. Commun. 10, 2693 (2019). This is primarily an in vitro study that demonstrates how the kinesin 3 effectors PTPN21 and HOOK3 both bind the tail domain of KIF1C to relieve motor autoinhibition.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Khobrekar, N. V., Quintremil, S., Dantas, T. J. & Vallee, R. B. The dynein adaptor RILP controls neuronal autophagosome biogenesis, transport, and clearance. Dev. Cell https://doi.org/10.1016/j.devcel.2020.03.011 (2020).

    Article  PubMed  Google Scholar 

  121. Lie, P. P. Y. et al. Post-Golgi carriers, not lysosomes, confer lysosomal properties to pre-degradative organelles in normal and dystrophic axons. Cell Rep. 35, 109034 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Spinner, M. A., Pinter, K., Drerup, C. M. & Herman, T. G. A conserved role for vezatin proteins in cargo-specific regulation of retrograde axonal transport. Genetics 216, 431–445 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Farías, G. G., Guardia, C. M., Pace, R. D., Britt, D. J. & Bonifacino, J. S. BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon. Proc. Natl Acad. Sci. USA 114, E2955–E2964 (2017). This work demonstrates that the BORC–ARL8–SKIP complex is important for kinesin 1-driven transport of lysosomes specifically in mammalian axons.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Pu, J. et al. BORC, a multisubunit complex that regulates lysosome positioning. Dev. Cell 33, 176–188 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Cheng, X.-T. et al. Characterization of LAMP1-labeled nondegradative lysosomal and endocytic compartments in neurons. J. Cell Biol. 217, 3127–3139 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Cai, Q. et al. Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons. Neuron 68, 73–86 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Shi, B. et al. SNAPIN is critical for lysosomal acidification and autophagosome maturation in macrophages. Autophagy 13, 285–301 (2017).

    Article  CAS  PubMed  Google Scholar 

  128. Willett, R. et al. TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes. Nat. Commun. 8, 1580 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Gowrishankar, S., Wu, Y. & Ferguson, S. M. Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology. J. Cell Biol. 216, 3291–3305 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Gowrishankar, S. et al. Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons. Mol. Biol. Cell. https://doi.org/10.1091/mbc.E20-06-0382 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Drerup, C. M. & Nechiporuk, A. V. JNK-interacting protein 3 mediates the retrograde transport of activated c-Jun N-terminal kinase and lysosomes. PLoS Genet. 9, e1003303 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kumar, G. et al. RUFY3 links Arl8b and JIP4-dynein complex to regulate lysosome size and positioning. Nat. Commun. 13, 1540 (2022). This study identifies a novel effector of dynein-driven transport of endolysosomes, RUFY3, that links the cargo with the dynein effector JIP4 to induce transport.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Keren-Kaplan, T. et al. RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin. Nat. Commun. 13, 1506 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Arimoto, M. et al. The Caenorhabditis elegans JIP3 protein UNC-16 functions as an adaptor to link kinesin-1 with cytoplasmic dynein. J. Neurosci. 31, 2216–2224 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Celestino, R. et al. JIP3 regulates bi-directional organelle transport in neurons through its interaction with dynein and kinesin-1. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/2021.10.11.463801v1 (2021)

  136. Ganguly, A. et al. Clathrin packets move in slow axonal transport and deliver functional payloads to synapses. Neuron 109, 2884–2901.e7 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Guedes-Dias, P. et al. Kinesin-3 responds to local microtubule dynamics to target synaptic cargo delivery to the presynapse. Curr. Biol. 29, 268–282.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Aiken, J. & Holzbaur, E. L. F. Cytoskeletal regulation guides neuronal trafficking to effectively supply the synapse. Curr. Biol. 31, R633–R650 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Dalla Costa, I. et al. The functional organization of axonal mRNA transport and translation. Nat. Rev. Neurosci. 22, 77–91 (2021).

    Article  CAS  PubMed  Google Scholar 

  140. Juranek, J. K., Mukherjee, K., Jahn, R. & Li, J.-Y. Coordinated bi-directional trafficking of synaptic vesicle and active zone proteins in peripheral nerves. Biochem. Biophys. Res. Commun. 559, 92–98 (2021).

    Article  CAS  PubMed  Google Scholar 

  141. Okada, Y., Yamazaki, H., Sekine-Aizawa, Y. & Hirokawa, N. The neuron-specific kinesin superfamily protein KIF1A is a uniqye monomeric motor for anterograde axonal transport of synaptic vesicle precursors. Cell 81, 769–780 (1995).

    Article  CAS  PubMed  Google Scholar 

  142. Qu, X., Kumar, A., Blockus, H., Waites, C. & Bartolini, F. Activity-dependent nucleation of dynamic microtubules at presynaptic boutons controls neurotransmission. Curr. Biol. 29, 4231–4240.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Klopfenstein, D. R. & Vale, R. D. The lipid binding pleckstrin homology domain in UNC-104 kinesin is necessary for synaptic vesicle transport in caenorhabditis elegans. Mol. Biol. Cell 15, 3729–3739 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Vukoja, A. et al. Presynaptic biogenesis requires axonal transport of lysosome-related vesicles. Neuron 99, 1216–1232.e7 (2018).

    Article  CAS  PubMed  Google Scholar 

  145. Klassen, M. P. et al. An Arf-like small G protein, ARL-8, promotes the axonal transport of presynaptic cargoes by suppressing vesicle aggregation. Neuron 66, 710–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Choudhary, B. et al. UNC-16/JIP3 regulates early events in synaptic vesicle protein trafficking via LRK-1/LRRK2 and AP complexes. PLoS Genet. 13, e1007100 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Watt, D., Dixit, R. & Cavalli, V. JIP3 activates kinesin-1 motility to promote axon elongation. J. Biol. Chem. 290, 15512–15525 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Wong, M. Y. et al. Neuropeptide delivery to synapses by long-range vesicle circulation and sporadic capture. Cell 148, 1029–1038 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Bharat, V. et al. Capture of dense core vesicles at synapses by JNK-dependent phosphorylation of synaptotagmin-4. Cell Rep. 21, 2118–2133 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Stucchi, R. et al. Regulation of KIF1A-driven dense core vesicle transport: Ca2+/CaM controls DCV binding and liprin-α/TANC2 recruits DCVs to postsynaptic sites. Cell Rep. 24, 685–700 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Emperador-Melero, J. & Kaeser, P. S. Assembly of the presynaptic active zone. Curr. Opin. Neurobiol. 63, 95–103 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Chua, J. J. E. et al. Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a kinesin-1 adapter. Proc. Natl Acad. Sci. USA 109, 5862–5867 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Blasius, T. L., Cai, D., Jih, G. T., Toret, C. P. & Verhey, K. J. Two binding partners cooperate to activate the molecular motor kinesin-1. J. Cell Biol. 176, 11–17 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Barber, K. R. et al. Active zone proteins are transported via distinct mechanisms regulated by Par-1 kinase. PLoS Genet. 13, e1006621 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Fu, M., Nirschl, J. J. & Holzbaur, E. L. F. LC3 binding to the scaffolding protein JIP1 regulates processive dynein-driven transport of autophagosomes. Dev. Cell 29, 577–590 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Shirasaki, D. I. et al. Network organization of the huntingtin proteomic interactome in mammalian brain. Neuron 75, 41–57 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Wong, Y. C. & Holzbaur, E. L. F. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J. Neurosci. 34, 1293–1305 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Twelvetrees, A. E. et al. Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron 65, 53–65 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Hill, S. E. et al. Maturation and clearance of autophagosomes in neurons depends on a specific cysteine protease isoform, ATG-4.2. Dev. Cell 49, 251–266.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. George, A. A., Hayden, S., Stanton, G. R. & Brockerhoff, S. E. Arf6 and the 5′phosphatase of synaptojanin 1 regulate autophagy in cone photoreceptors. BioEssays 38, S119–S135 (2016).

    Article  CAS  PubMed  Google Scholar 

  161. Cason, S. E., Mogre, S. S., Holzbaur, E. L. F. & Koslover, E. F. Spatiotemporal analysis of axonal autophagosome-lysosome dynamics reveals limited fusion events trigger two-step maturation. Preprint at bioRxiv https://doi.org/10.1101/2022.02.17.480915 (2022).

    Article  Google Scholar 

  162. Cheng, X.-T., Zhou, B., Lin, M.-Y., Cai, Q. & Sheng, Z.-H. Axonal autophagosomes recruit dynein for retrograde transport through fusion with late endosomes. J. Cell Biol. 209, 377–386 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Deinhardt, K. et al. Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway. Neuron 52, 293–305 (2006).

    Article  CAS  PubMed  Google Scholar 

  164. Zanin, J. P., Montroull, L. E., Volosin, M. & Friedman, W. J. The p75 neurotrophin receptor facilitates TrkB signaling and function in rat hippocampal neurons. Front. Cell. Neurosci. 13, 485 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Lim, Y. et al. HAP1 is required for endocytosis and signalling of BDNF and its receptors in neurons. Mol. Neurobiol. 55, 1815–1830 (2018).

    Article  CAS  PubMed  Google Scholar 

  166. Yao, X., Arst, H. N., Wang, X. & Xiang, X. Discovery of a vezatin-like protein for dynein-mediated early endosome transport. Mol. Biol. Cell. 26, 3816–3827 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Budzinska, M. I. et al. PTPN23 binds the dynein adaptor BICD1 and is required for endocytic sorting of neurotrophin receptors. J. Cell Sci. 133, jcs242412 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Terenzio, M., Golding, M. & Schiavo, G. siRNA screen of ES cell-derived motor neurons identifies novel regulators of tetanus toxin and neurotrophin receptor trafficking. Front. Cell. Neurosci. 8, 140 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Zhou, B., Cai, Q., Xie, Y. & Sheng, Z.-H. Snapin recruits dynein to BDNF-TrkB signaling endosomes for retrograde axonal transport and is essential for dendrite growth of cortical neurons. Cell Rep. 2, 42–51 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Hendricks, A. G., Holzbaur, E. L. F. & Goldman, Y. E. Force measurements on cargoes in living cells reveal collective dynamics of microtubule motors. Proc. Natl Acad. Sci. USA 109, 18447–18452 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Zanacchi, F. C., Manzo, C., Magrassi, R., Derr, N. D. & Lakadamyali, M. Quantifying protein copy number in super resolution using an imaging-invariant calibration. Biophys. J. 116, 2195–2203 (2019).

    Article  Google Scholar 

  172. Rosa-Ferreira, C., Sweeney, S. T. & Munro, S. The small G protein Arl8 contributes to lysosomal function and long-range axonal transport in Drosophila. Biol. Open 7, bio035964 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  173. McKenney, R. J., Huynh, W., Vale, R. D. & Sirajuddin, M. Tyrosination of α-tubulin controls the initiation of processive dynein–dynactin motility. EMBO J. 35, 1175–1185 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Reed, N. A. et al. Microtubule acetylation promotes kinesin-1 binding and transport. Curr. Biol. 16, 2166–2172 (2006).

    Article  CAS  PubMed  Google Scholar 

  175. Balabanian, L., Berger, C. L. & Hendricks, A. G. Acetylated microtubules are preferentially bundled leading to enhanced kinesin-1 motility. Biophys. J. 113, 1551–1560 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Kaul, N., Soppina, V. & Verhey, K. J. Effects of α-tubulin K40 acetylation and detyrosination on kinesin-1 motility in a purified system. Biophys. J. 106, 2636–2643 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Karasmanis, E. P. et al. Polarity of neuronal membrane traffic requires sorting of kinesin motor cargo during entry into dendrites by a microtubule-associated septin. Dev. Cell 46, 204–218.e7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Aiken, J., Moore, J. K. & Bates, E. A. TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity. Hum. Mol. Genet. 28, 1227–1243 (2019).

    Article  CAS  PubMed  Google Scholar 

  179. Lopes, A. T. et al. Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits. PLOS Biol. 18, e3000820 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Vemu, A. et al. Severing enzymes amplify microtubule arrays through lattice GTP-tubulin incorporation. Science 361, eaau1504 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Fumagalli, L. et al. C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility. Sci. Adv. 7, eabg3013 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Sabblah, T. T. et al. A novel mouse model carrying a human cytoplasmic dynein mutation shows motor behavior deficits consistent with Charcot-Marie-Tooth type 2O disease. Sci. Rep. 8, 1739 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Peeters, K. et al. Novel mutations in the DYNC1H1 tail domain refine the genetic and clinical spectrum of dyneinopathies. Hum. Mutat. 36, 287–291 (2015).

    Article  CAS  PubMed  Google Scholar 

  184. Dutta, M., Diehl, M. R., Onuchic, J. N. & Jana, B. Structural consequences of hereditary spastic paraplegia disease-related mutations in kinesin. Proc. Natl Acad. Sci. USA 115, E10822–E10829 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Nicolas, A. et al. Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron 97, 1268–1283.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Nakamura, R. et al. Genetic and functional analysis of KIF5A variants in Japanese patients with sporadic amyotrophic lateral sclerosis. Neurobiol. Aging 97, 147.e11–147.e17 (2021).

    Article  CAS  Google Scholar 

  187. Guo, Y. et al. A rare KIF1A missense mutation enhances synaptic function and increases seizure activity. Front. Genet. 11, 61 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Aguilera, C. et al. The novel KIF1A missense variant (R169T) strongly reduces microtubule stimulated ATPase activity and is associated with NESCAV syndrome. Front. Neurosci. 15, 618098 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Gabrych, D. R., Lau, V. Z., Niwa, S. & Silverman, M. A. Going too far is the same as falling short†: kinesin-3 family members in hereditary spastic paraplegia. Front. Cell. Neurosci. 13, 419 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Chiba, K. et al. Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors. Proc. Natl Acad. Sci. USA 116, 18429–18434 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Asselin, L. et al. Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity. Nat. Commun. 11, 2441 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Giaime, E. et al. Age-dependent dopaminergic neurodegeneration and impairment of the autophagy-lysosomal pathway in LRRK-deficient mice. Neuron 96, 796–807.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Roney, J. C. et al. Lipid-mediated motor-adaptor sequestration impairs axonal lysosome delivery leading to autophagic stress and dystrophy in Niemann-Pick type C. Dev. Cell 56, 1452–1468.e8 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grants R35 GM126950 and RM1 GM136511 to E.L.F.H. and an NSF Graduate Research Fellowship (DGE-1845298) to S.E.C. The authors declare no competing financial interests. They thank J. Aiken and A. Fenton for insights and discussions.

Author information

Authors and Affiliations

  1. Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Sydney E. Cason & Erika L. F. Holzbaur

  2. Neuroscience Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Sydney E. Cason & Erika L. F. Holzbaur

  3. Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Sydney E. Cason & Erika L. F. Holzbaur

Authors
  1. Sydney E. Cason
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erika L. F. Holzbaur
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.C. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Erika L. F. Holzbaur.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Molecular Cell Biology thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Signalling endosomes

Membranous organelles formed by internalizing a neurotrophin-bound receptor, which is then trafficked to the soma to trigger downstream effects, including transcriptional changes. Following signalling, the receptor may be degraded or recycled back to the plasma membrane.

Coiled-coil

(CC). Structural motif in which multiple α-helices are coiled together to form a supercoil. The primary sequence is made up of a series of heptad repeats including both hydrophobic and charged residues. CC domains are often stiff rods that function as molecular spacers.

Dynein-activating adaptors

Dynein effectors that activate dynein motility and link dynein — directly or indirectly — to cargo. Most dynein-activating adaptors contain an extended coiled-coil motif (~38 nm) flanked by conserved motifs for dynein and dynactin binding.

Tetratricopeptide repeats

(TPRs). Common structural motifs consisting of 3–16 tandem repeats that form α-helices, which typically fold together to form a leaner solenoid domain. The TPR motif in kinesin light chain is commonly the binding site for kinesin 1-activating proteins.

Leucine–phenylalanine–proline (LFP) motif

A short unstructured motif (also referred to as an ‘LFP–acidic motif’) involved in protein–protein interactions. The LFP motif in kinesin light chain is commonly the binding site for kinesin 1-activating proteins.

Hereditary spastic paraplegia

A group of rare inherited peripheral nerve disorders characterized by weakness and stiffness of the leg muscles which progress over time.

Amyotrophic lateral sclerosis

Also known as Lou Gehrig disease, a progressive nervous system disease resulting in muscle weakness and other motor symptoms. The causes differ, and onset is typically between 40 years of age and 65 years of age.

Phox homology (PX) or pleckstrin homology (PH) domains

Lipid-binding domains that interact with phosphoinositides, facilitating membrane localization.

ARP1 filament

Dynactin sub-complex consisting of a filament made up of actin-related protein 1 (ARP1), a pointed-end complex (ARP11, p62, p25 and p27) and a barbed-end complex (CapZα and CapZβ).

p150Glued

Dynactin subunit protein containing a microtubule-binding CAP-Gly domain and a globular shoulder domain connected by a flexible coiled-coil-enriched linker domain.

CC1 box motif

Common dynein-activating adaptor motif that forms a hydrophobic pocket in which the dynein light intermediate chain helix 1 inserts itself.

Spindly motif

Common dynein-activating adaptor motif that mediates interaction with the pointed-end complex of the ARP1 filament of dynactin.

Glued motif

Common dynein-activating adaptor motif that mediates interaction with the second coiled-coil domain of the p150Glued subunit of dynactin.

O-GlcNAcylation

A reversible post-translational modification whereby a monosaccharide (O-linked β-N-acetylglucosamine (O-GlcNAc)) is attached to a serine or threonine residue. O-GlcNAcylation typically occurs in response to changes in nutrient state or stress.

Active zone

The region of the presynapse where synaptic vesicle fusion and neurotransmitter release occur.

En passant synapses

Presynapses located along the axon shaft.

Axon initial segment

The short region (20–60 µm) of the axon immediately adjacent to the soma which acts as a selective filter to limit axonal transport and initiates action potentials (electrical signalling).

Calmodulin

A secondary messenger protein activated by the binding of Ca2+ involved in numerous cell signalling pathways.

JNK

(JUN amino-terminal kinase). A family of mitogen-activated protein kinases that respond to stress stimuli and trigger signalling cascades implicated in inflammation, gene expression, DNA repair, neuronal plasticity, and cell death or senescence.

Piccolo–Bassoon transport vesicles

trans-Golgi-derived vesicles that transport Piccolo and Bassoon, two large scaffolding proteins that help form the active zone, from the soma to the presynapses.

Amyloid precursor protein

(APP). A transmembrane protein enriched at synapses believed to be important for synaptic formation and plasticity. APP can be differentially cleaved, and the cleavage product, β-amyloid, accumulates in neurodegenerative diseases, including Alzheimer disease.

Huntingtin

(HTT). A large scaffolding protein (~350 kDa) involved in multiple pathways, including axonal transport and transcription. Expansion of the polyglutamine repeat region in the amino terminus of the protein results in Huntington disease.

AKT

Also known as protein kinase B, a family of serine/threonine kinases involved in cell survival, proliferation and metabolism.

ATG8

A family of ubiquitin-like proteins localized primarily to the autophagosomal membrane and necessary for both selective and bulk autophagy, autophagosome biogenesis and autophagosome–lysosome fusion. LC3B is a well-characterized member of this family commonly used as a marker for autophagosomes in mammalian cells.

Neurotrophin

Extracellular-signalling factor (typically a small protein or peptide) that triggers cascades in neurons, including to survival, development/growth and function.

Spinal muscular atrophy with lower-extremity predominance

An inherited neuromuscular disorder characterized by muscle weakness and wasting in the lower limbs, which primarily appears in childhood.

Lissencephaly

A neurodevelopmental disorder characterized by a ‘smooth brain’ without normal cortical folds.

Microcephaly

A birth defect wherein a baby’s head is smaller than normal owing to abnormal brain development.

Huntington disease

A neurodegenerative disease resulting from a polyglutamine expansion in the gene encoding huntingtin (HTT). Symptoms typically appear in early adulthood, include both motor and cognitive problems, and worsen over time.

Parkinson disease

A progressive neurodegenerative disease resulting from the degradation of the dopaminergic neurons in the substantia nigra, part of the midbrain. Symptoms include tremors, stiffness and difficulty moving, especially controlling or initiating movement.

Lysosomal storage disorder

A class of inherited metabolic disorders wherein lysosomal degradation is defective. They can affect a range of tissues, including the brain, eyes, muscles and kidneys. Most patients develop symptoms during childhood, and these worsen over time.

ESCRT

Endosomal sorting complexes required for transport (0–III) made up of cytosolic proteins that facilitate membrane remodelling including, multivesicular body formation and membrane abscission during cytokinesis. They can also be involved in protein–protein interactions, especially to recruit other proteins to the endosomal membrane.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cason, S.E., Holzbaur, E.L.F. Selective motor activation in organelle transport along axons. Nat Rev Mol Cell Biol 23, 699–714 (2022). https://doi.org/10.1038/s41580-022-00491-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-022-00491-w

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing