Emerging mechanisms of dynein transport in the cytoplasm versus the cilium

Abstract

Two classes of dynein power long-distance cargo transport in different cellular contexts. Cytoplasmic dynein-1 is responsible for the majority of transport toward microtubule minus ends in the cell interior. Dynein-2, also known as intraflagellar transport dynein, moves cargoes along the axoneme of eukaryotic cilia and flagella. Both dyneins operate as large ATP-driven motor complexes, whose dysfunction is associated with a group of human disorders. But how similar are their mechanisms of action and regulation? To examine this question, this review focuses on recent advances in dynein-1 and -2 research, and probes to what extent the emerging principles of dynein-1 transport could apply to or differ from those of the less well-understood dynein-2 mechanoenzyme.

LIS1 regulates cargo-adapter–mediated activation of dynein by overcoming its autoinhibition in vivo

“…LIS1 is required for cytoplasmic dynein function in many different cell types (Kardon and Vale, 2009;Vallee et al, 2012;. Possibly, it also regulates dynein inside cilia/flagella, where dynactin is absent, since LIS1 is associated with outer-arm dynein required for flagellar beating, and the intraflagella transport dynein-2 is regulated by a philike autoinhibited state (Pedersen et al, 2007;Rompolas et al, 2012;Toropova et al, 2017;Roberts, 2018). Our results on the positive role of LIS1 in dynein activation are consistent with the results that LIS1 enhances the speed and/or frequency of dynein motility to varying extents in different in vitro motility assays in the presence of dynactin and the N-terminal portion of the cargo adapter BicD2 (Baumbach et al, 2017;Gutierrez et al, 2017;Jha et al, 2017).…”

The Generation of Dynein Networks by Multi-Layered Regulation and Their Implication in Cell Division

“…A mutant dynein with a defect in phi-particle formation was found to accumulate at the centrosome and the spindle pole, suggesting that phiparticle-based autoinhibition plays a role in the intracellular distribution of dynein (Zhang et al, 2017). Interestingly, recent studies have shown that cytoplasmic dynein-2, which is responsible for intraflagellar transport (IFT), forms a phiparticle-like conformation (Toropova et al, 2017;Jordan et al, 2018), suggesting that the formation of phi-particles is a conserved regulatory mechanism of dimeric dyneins (Roberts, 2018). In order to act as a processive motor, the dynein complex needs to interact with other proteins, such as the dynactin complex, as will be explained in the following section on layer 3.…”

“…In many eukaryotic cells, cytoplasmic dynein is responsible for most of the minus-end directed motion inside the cell (Pfister et al, 2006;Wickstead and Gull, 2007;Kardon and Vale, 2009;Roberts et al, 2013), whereas kinesin is mainly responsible for plus-end directed motion. Cytoplasmic dynein-1 transports several types of cargos, such as vesicles, membranous organelles, mRNA, and viruses (Dodding and Way, 2011;Reck-Peterson et al, 2018), whereas cytoplasmic dynein-2 is responsible for retrograde transport in the cilia and flagella (Hou and Witman, 2015;Roberts, 2018). A striking feature of cytoplasmic dynein-1 is that, despite the wide variety of its function, the heavy chain polypeptide (catalytic subunit) of cytoplasmic dynein-1 is coded in a single gene (Pfister et al, 2006).…”

“…Kinesin isoforms are differentially expressed according to the cell cycle, whereas a single heavy chain of dynein is responsible for a variety of cellular processes throughout the cell cycle (Kobayashi and Murayama, 2009). An increasing understanding of cytoplasmic dynein-1 suggests the existence of various kinds of dynein with different molecular compositions and functions share a common catalytic subunit (heavy chain) to achieve various cellular activities (Cianfrocco et al, 2015;Reck-Peterson et al, 2018;Roberts, 2018;Olenick and Holzbaur, 2019). In this review, we refer to the various kinds of cytoplasmic dynein-1 as "dyneins."…”

Insights into LIS1 function in cargo-adapter-mediated dynein activation in vivo

“…LIS1 is required for cytoplasmic dynein function in many different cell types (Kardon and Vale, 2009;Vallee et al, 2012;. Possibly, it also regulates dynein inside cilia and flagella where a phi-like state of dynein is present (Pedersen et al, 2007;Rompolas et al, 2012;Toropova et al, 2017;Roberts, 2018). Recent studies have shown that the function of LIS1 is context-dependent (Yamada et al, 2008;McKenney et al, 2010;Huang et al, 2012;Wang et al, 2013;Baumbach et al, 2017;DeSantis et al, 2017;Gutierrez et al, 2017;Jha et al, 2017).…”