Anomalous intracellular transport phases depend on cytoskeletal network features

Maelfeyt, Bryan; Tabei, S. M. Ali; Gopinathan, Ajay

doi:10.1103/physreve.99.062404

Cited by 9 publications

(12 citation statements)

References 43 publications

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“…This would be inconsistent with observations that both the MT network and granule motions on it are random. Instead, it is the topology of the MT network that influences cargo localization, not the specific motor dynamics (similar to (59,60)). Rather, the random but motor-driven granule motions observed in cells, coupled with the structured nature of the network near the membrane, are sufficient to generate directed motion of MT-bound granules away from the membrane.…”

Section: Discussionmentioning

confidence: 99%

Microtubules Regulate Localization and Availability of Insulin Granules in Pancreatic Beta Cells

Bracey

Yampolsky

et al. 2020

Biophysical Journal

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Two key prerequisites for glucose-stimulated insulin secretion (GSIS) in b cells are the proximity of insulin granules to the plasma membrane and their anchoring or docking to the plasma membrane (PM). Although recent evidence has indicated that both of these factors are altered in the context of diabetes, it is unclear what regulates localization of insulin granules and their interactions with the PM within single cells. Here, we demonstrate that microtubule (MT)-motor-mediated transport dynamics have a critical role in regulating both factors. Super-resolution imaging shows that whereas the MT cytoskeleton resembles a random meshwork in the cells' interior, MTs near the cell surface are preferentially aligned with the PM. Computational modeling suggests two consequences of this alignment. First, this structured MT network preferentially withdraws granules from the PM. Second, the binding and transport of insulin granules by MT motors prevents their stable anchoring to the PM. These findings suggest the MT cytoskeleton may negatively regulate GSIS by both limiting the amount of insulin proximal to the PM and preventing or breaking interactions between the PM and the remaining nearby insulin granules. These results predict that altering MT network structure in b cells can be used to tune GSIS. Thus, our study points to the potential of an alternative therapeutic strategy for diabetes by targeting specific MT regulators.

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Section: Discussionmentioning

confidence: 99%

Microtubules Regulate Localization and Availability of Insulin Granules in Pancreatic Beta Cells

Bracey

Yampolsky

et al. 2020

Biophysical Journal

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“…(5-10). Cellular-scale cargo distribution in these models generally relies on multimodal transport, incorporating processive runs whose direction is determined by the microtubule arrangement interspersed with pauses or diffusive phases that allow transition between microtubules (11,12). The microtubule architecture thus modulates transport efficiency both by directing processive motion and by determining the rate of capture for cargo in the passive state.…”

Section: Introductionmentioning

confidence: 99%

Optimizing microtubule arrangements for rapid cargo capture

Mogre

Christensen

Reck-Peterson

et al. 2021

Biophysical Journal

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Cellular functions such as autophagy, cell signaling, and vesicular trafficking involve the retrograde transport of motor-driven cargo along microtubules. Typically, newly formed cargo engages in slow undirected movement from its point of origin before attaching to a microtubule. In some cell types, cargo destined for delivery to the perinuclear region relies on capture at dynein-enriched loading zones located near microtubule plus ends. Such systems include extended cell regions of neurites and fungal hyphae, where the efficiency of the initial diffusive loading process depends on the axial distribution of microtubule plus ends relative to the initial cargo position. We use analytic mean first-passage time calculations and numerical simulations to model diffusive capture processes in tubular cells, exploring how the spatial arrangement of microtubule plus ends affects the efficiency of retrograde cargo transport. Our model delineates the key features of optimal microtubule arrangements that minimize mean cargo capture times. Namely, we show that configurations with a single microtubule plus end abutting the distal tip and broadly distributed other plus ends allow for efficient capture in a variety of different scenarios for retrograde transport. Livecell imaging of microtubule plus ends in Aspergillus nidulans hyphae indicates that their distributions exhibit these optimal qualitative features. Our results highlight important coupling effects between the distribution of microtubule tips and retrograde cargo transport, providing guiding principles for the spatial arrangement of microtubules within tubular cell regions.

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“…For disordered networks, the dependence of cargo delivery time on filament polarity, bundling, length, orientation, and local density has been established via continuum models and simulations of explicit network architectures [5–10]. Cellular-scale cargo distribution in these models generally relies on multimodal transport, incorporating processive runs whose direction is determined by the microtubule arrangement, intersperesed with diffusive or subdiffusive motion that allows transition between microtubules [11, 12]. The microtubule architecture thus modulates transport efficiency both by directing processive motion and by determining the rate of capture for cargo in the passive state.…”

Section: Introductionmentioning

confidence: 99%

Optimizing microtubule arrangements for rapid cargo capture

Mogre

Christensen

Reck-Peterson

et al. 2021

Preprint

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Cellular functions such as autophagy, cell signaling and vesicular trafficking involve the retrograde transport of motor-driven cargo along microtubules. Typically, newly formed cargo engages in slow diffusive movement from its point of origin before attaching to a microtubule. In some cell types, cargo destined for delivery to the perinuclear region relies on capture at dynein-enriched loading zones located near microtubule plus-ends. Such systems include extended cell regions of neurites and fungal hyphae, where the efficiency of the initial diffusive loading process depends on the axial distribution of microtubule plus-ends relative to the initial cargo position. We use analytic mean first passage time calculations and numerical simulations to model diffusive capture processes in tubular cells, exploring how the spatial arrangement of microtubule plus-ends affects the efficiency of retrograde cargo transport. Our model delineates the key features of optimal microtubule arrangements that minimize mean cargo capture times. Namely, we show that configurations with a single long microtubule and broad distribution of additional microtubule plus-ends allow for efficient capture in a variety of different scenarios for retrograde transport. Live-cell imaging of microtubule plus-ends in Aspergillus nidulans hyphae indicates that their distributions exhibit these optimal qualitative features. Our results highlight important coupling effects between microtubule length distribution and retrograde cargo transport, providing guiding principles for the spatial arrangement of microtubules within tubular cell regions.

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Anomalous intracellular transport phases depend on cytoskeletal network features

Cited by 9 publications

References 43 publications

Microtubules Regulate Localization and Availability of Insulin Granules in Pancreatic Beta Cells

Microtubules Regulate Localization and Availability of Insulin Granules in Pancreatic Beta Cells

Optimizing microtubule arrangements for rapid cargo capture

Optimizing microtubule arrangements for rapid cargo capture

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