A dynein loading zone for retrograde endosome motility at microtubule plus-ends

Lenz, Jan-Heiko; Schuchardt, Isabel; Straube, Anne; Steinberg, Gero

doi:10.1038/sj.emboj.7601119

Cited by 218 publications

(504 citation statements)

References 47 publications

(102 reference statements)

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“…The Rab6a enriched region partially overlapped with the distribution of LIS1 ( Supplementary Fig. S1b), suggesting that they may be localized at a potential dynein-loading zone 29 . We assumed that dynamic regulation for dynein loading was carried out within this loading zone, and focused FCCS examination onto the loading zone in the DRG neurons.…”

Section: Resultsmentioning

confidence: 94%

Rab6a releases LIS1 from a dynein idling complex and activates dynein for retrograde movement

et al. 2013

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Cytoplasmic dynein drives the movement of a wide range of cargoes towards the minus ends of microtubules. We previously demonstrated that LIS1 forms an idling complex with dynein, which is transported to the plus ends of microtubules by kinesin motors. Here we report that the small GTPase Rab6a is essential for activation of idling dynein. Immunoprecipitation and microtubule pull-down assays reveal that the GTP bound mutant, Rab6a(Q72L), dissociates LIS1 from a LIS1-dynein complex, activating dynein movement in in vitro microtubule gliding assays. We monitor transient interaction between Rab6a(Q72L) and dynein in vivo using dual-colour fluorescence cross-correlation spectroscopy in dorsal root ganglion (DRG) neurons. Finally, we demonstrate that Rab6a(Q72L) mediates LIS1 release from a LIS1-dynein complex followed by dynein activation through an in vitro single-molecule assay using triplecolour quantum dots. Our findings reveal a surprising function for GTP bound Rab6a as an activator of idling dynein.

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Section: Resultsmentioning

confidence: 94%

Rab6a releases LIS1 from a dynein idling complex and activates dynein for retrograde movement

et al. 2013

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“…Lis1 is well known to be involved in the initiation of dynein‐dependent transport in cells (Lenz et al , 2006; Egan et al , 2012; Moughamian et al , 2013). Reducing Lis1 levels in fungi and mammalian cells inhibits dynein‐dependent transport of several organelles (Pandey & Smith, 2011; Egan et al , 2012; Dix et al , 2013; Moughamian et al , 2013; Klinman & Holzbaur, 2015) and BicD2‐N carrying vesicles (Splinter et al , 2012) in agreement with the simultaneous requirement of Lis1 and BicD2 for transport initiation as observed in our minimal system.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial regulation of the balance between dynein microtubule end accumulation and initiation of directed motility

et al. 2017

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Cytoplasmic dynein is involved in a multitude of essential cellular functions. Dynein's activity is controlled by the combinatorial action of several regulatory proteins. The molecular mechanism of this regulation is still poorly understood. Using purified proteins, we reconstitute the regulation of the human dynein complex by three prominent regulators on dynamic microtubules in the presence of end binding proteins (EBs). We find that dynein can be in biochemically and functionally distinct pools: either tracking dynamic microtubule plus‐ends in an EB‐dependent manner or moving processively towards minus ends in an adaptor protein‐dependent manner. Whereas both dynein pools share the dynactin complex, they have opposite preferences for binding other regulators, either the adaptor protein Bicaudal‐D2 (BicD2) or the multifunctional regulator Lissencephaly‐1 (Lis1). BicD2 and Lis1 together control the overall efficiency of motility initiation. Remarkably, dynactin can bias motility initiation locally from microtubule plus ends by autonomous plus‐end recognition. This bias is further enhanced by EBs and Lis1. Our study provides insight into the mechanism of dynein regulation by dissecting the distinct functional contributions of the individual members of a dynein regulatory network.

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“…The available evidence suggests that they are involved in long-range transport of vesicles to the hyphal tip region (Horio and Oakley, 2005, and other data discussed therein; Lenz et al, 2006). Note that there is considerable evidence that microtubules are extremely dynamic at the hyphal tip (Han et al, 2001;Szewczyk, Symeonidou-Sideris, and Oakley, unpublished data), continually growing and shrinking.…”

Section: Functions Of Cytoskeletal Elementsmentioning

confidence: 99%

“…Secretory vesicles are transported by kinesins (including type 3 kinesins; Lenz et al, 2006) on microtubules to the tip region where they leave the microtubules and become associated with actin cables, the assembly of which is nucleated by the formin SEPA. Vesicles could fall off the microtubules and then become attached to myosin before moving along actin cables; alternatively, they could be transferred directly from microtubules to actin cables.…”

Section: An Integrated Model For Hyphal Tip Growthmentioning

confidence: 99%

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The Tip Growth Apparatus ofAspergillus nidulans

Taheri-Talesh

Horio

Araújo‐Bazán

et al. 2008

MBoC

274

414

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Hyphal tip growth in fungi is important because of the economic and medical importance of fungi, and because it may be a useful model for polarized growth in other organisms. We have investigated the central questions of the roles of cytoskeletal elements and of the precise sites of exocytosis and endocytosis at the growing hyphal tip by using the model fungus Aspergillus nidulans. Time-lapse imaging of fluorescent fusion proteins reveals a remarkably dynamic, but highly structured, tip growth apparatus. Live imaging of SYNA, a synaptobrevin homologue, and SECC, an exocyst component, reveals that vesicles accumulate in the Spitzenkö rper (apical body) and fuse with the plasma membrane at the extreme apex of the hypha. SYNA is recycled from the plasma membrane by endocytosis at a collar of endocytic patches, 1-2 m behind the apex of the hypha, that moves forward as the tip grows. Exocytosis and endocytosis are thus spatially coupled. Inhibitor studies, in combination with observations of fluorescent fusion proteins, reveal that actin functions in exocytosis and endocytosis at the tip and in holding the tip growth apparatus together. Microtubules are important for delivering vesicles to the tip area and for holding the tip growth apparatus in position. INTRODUCTIONPolarized cell growth occurs in most eukaryotic phyla, and it includes a plethora of important phenomena, such as neuronal growth cone extension in animals and pollen tube extension in vascular plants. It is particularly important in filamentous fungi where nearly all growth occurs by hyphal tip extension (reviewed by Momany, 2002). Given that some filamentous fungi are important fermentation organisms, the growth of which is of considerable economic importance, whereas others are serious plant, animal, and human pathogens, there is considerable interest in the mechanisms of tip growth in these organisms.A great deal of progress has been made in understanding fungal tip growth (summarized by Harris et al., 2005; Steinberg, 2007a,b;Riquelme et al., 2007), but key questions remain unanswered. There is general agreement that fungal tip growth involves the synthesis of cell wall components in the cell body, the incorporation of these components into vesicles, the transport of these vesicles to the cell tip, the fusion of these vesicles with the plasma membrane in the area of the cell tip (exocytosis) to release their contents, and the cross-linking of the components after release. It is clear that both microtubules and actin microfilaments play important roles in fungal tip growth, but their exact functions are not yet defined. The exact sites of exocytosis and endocytosis also remain to be determined. The positions of the site(s) of exocytosis are particularly important because fungal walls are relatively stiff structures, and once they have formed the shape of the hypha is established. Hyphal shape is thus determined to a very significant extent by where the wall precursors are released from the cytoplasm, i.e., by the positioning of the site(s) of exocyto...

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A dynein loading zone for retrograde endosome motility at microtubule plus-ends

Cited by 218 publications

References 47 publications

Rab6a releases LIS1 from a dynein idling complex and activates dynein for retrograde movement

Rab6a releases LIS1 from a dynein idling complex and activates dynein for retrograde movement

Combinatorial regulation of the balance between dynein microtubule end accumulation and initiation of directed motility

The Tip Growth Apparatus ofAspergillus nidulans

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