A Stochastic Model for Microtubule Motors Describes the In Vivo Cytoplasmic Transport of Human Adenovirus

Gazzola, Mattia; Burckhardt, Christoph J.; Bayati, Basil; Engelke, Martin F.; Greber, Urs F.; Koumoutsakos, Petros

doi:10.1371/journal.pcbi.1000623

Cited by 52 publications

(63 citation statements)

References 44 publications

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“…The motors bind rather weakly and in low copy numbers to the adenovirus particles (Bremner et al, 2009;Gazzola et al, 2009). Accordingly, microtubule-dependent adenovirus motion bursts are rare, amounting to a few percent of the life time of the virions in the cytosol Helmuth et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

The nuclear export factor CRM1 controls juxta-nuclear microtubule-dependent virus transport

Wang

Burckhardt

Yakimovich

et al. 2017

Journal of Cell Science

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Transport of large cargo through the cytoplasm requires motor proteins and polarized filaments. Viruses that replicate in the nucleus of post-mitotic cells use microtubules and the dynein-dynactin motor to traffic to the nuclear membrane and deliver their genome through nuclear pore complexes (NPCs) into the nucleus. How virus particles (virions) or cellular cargo are transferred from microtubules to the NPC is unknown. Here, we analyzed trafficking of incoming cytoplasmic adenoviruses by single-particle tracking and superresolution microscopy. We provide evidence for a regulatory role of CRM1 (chromosome-region-maintenance-1; also known as XPO1, exportin-1) in juxta-nuclear microtubule-dependent adenovirus transport. Leptomycin B (LMB) abolishes nuclear targeting of adenovirus. It binds to CRM1, precludes CRM1-cargo binding and blocks signal-dependent nuclear export. LMB-inhibited CRM1 did not compete with adenovirus for binding to the nucleoporin Nup214 at the NPC. Instead, CRM1 inhibition selectively enhanced virion association with microtubules, and boosted virion motions on microtubules less than ∼2 µm from the nuclear membrane. The data show that the nucleus provides positional information for incoming virions to detach from microtubules, engage a slower microtubule-independent motility to the NPC and enhance infection.

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Section: Discussionmentioning

confidence: 99%

The nuclear export factor CRM1 controls juxta-nuclear microtubule-dependent virus transport

Wang

Burckhardt

Yakimovich

et al. 2017

Journal of Cell Science

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“…This is followed by receptor-mediated endocytosis (70) and enables virus escape from endosomes (34). The cytosolic viruses traffic on microtubules using the dynein/dynactin motor complex to reach the nucleus (12,29,35,54,99). They dock to the nuclear pore complex, disassemble by a kinesin motormediated disruption process, and release the viral genome into the nucleus (98,106).…”

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confidence: 99%

Cell-Free Transmission of Human Adenovirus by Passive Mass Transfer in Cell Culture Simulated in a Computer Model

Yakimovich

Gumpert

Burckhardt

et al. 2012

J Virol

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130

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Viruses spread between cells, tissues, and organisms by cell-free and cell-cell transmissions. Both mechanisms enhance disease development, but it is difficult to distinguish between them. Here, we analyzed the transmission mode of human adenovirus (HAdV) in monolayers of epithelial cells by wet laboratory experimentation and a computer simulation. Using live-cell fluorescence microscopy and replication-competent HAdV2 expressing green fluorescent protein, we found that the spread of infection invariably occurred after cell lysis. It was affected by convection and blocked by neutralizing antibodies but was independent of second-round infections. If cells were overlaid with agarose, convection was blocked and round plaques developed around lytic infected cells. Infected cells that did not lyse did not give rise to plaques, highlighting the importance of cell-free transmission. Key parameters for cell-free virus transmission were the time from infection to lysis, the dose of free viruses determining infection probability, and the diffusion of single HAdV particles in aqueous medium. With these parameters, we developed anin silicomodel using multiscale hybrid dynamics, cellular automata, and particle strength exchange. This so-called white box model is based on experimentally determined parameters and reproduces viral infection spreading as a function of the local concentration of free viruses. These analyses imply that the extent of lytic infections can be determined by either direct plaque assays or can be predicted by calculations of virus diffusion constants and modeling.

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“…Although multiple kinesin motors to transport one carrier vesicle is accepted, the number of active kinesins is believed to be less than 10, supported by experiments and mathematical modeling (Erickson et al, 2011;Shubeita et al, 2008;Gazzola et al, 2009). In sharp contrast, despite all the caveats , our quantitative microscopy data suggest that in the presence of Kv3.1 one anterograde transporting vesicle can astonishingly contain up to 200 motor dimers (Fig.…”

Section: Regulation Of the Copy Number Of Kif5 Motors On A Transportimentioning

confidence: 54%

Activation of conventional kinesin motors in clusters by shaw voltage-gated potassium channels

Barry

et al. 2013

Journal of Cell Science

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SummaryThe conventional kinesin motor transports many different cargos to specific locations in neurons. How cargos regulate motor function remains unclear. Here we focus on KIF5, the heavy chain of conventional kinesin, and report that the Kv3 (Shaw) voltage-gated K + channel, the only known tetrameric KIF5-binding protein, clusters and activates KIF5 motors during axonal transport. Endogenous KIF5 often forms clusters along axons, suggesting a potential role of KIF5-binding proteins. Our biochemical assays reveal that the highaffinity multimeric binding between the Kv3.1 T1 domain and KIF5B requires three basic residues in the KIF5B tail. Kv3.1 T1 competes with the motor domain and microtubules, but not with kinesin light chain 1 (KLC1), for binding to the KIF5B tail. Live-cell imaging assays show that four KIF5-binding proteins, Kv3.1, KLC1 and two synaptic proteins SNAP25 and VAMP2, differ in how they regulate KIF5B distribution. Only Kv3.1 markedly increases the frequency and number of KIF5B-YFP anterograde puncta. Deletion of Kv3.1 channels reduces KIF5 clusters in mouse cerebellar neurons. Therefore, clustering and activation of KIF5 motors by Kv3 regulate the motor number in carrier vesicles containing the channel proteins, contributing not only to the specificity of Kv3 channel transport, but also to the cargo-mediated regulation of motor function.

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A Stochastic Model for Microtubule Motors Describes the In Vivo Cytoplasmic Transport of Human Adenovirus

Cited by 52 publications

References 44 publications

The nuclear export factor CRM1 controls juxta-nuclear microtubule-dependent virus transport

The nuclear export factor CRM1 controls juxta-nuclear microtubule-dependent virus transport

Cell-Free Transmission of Human Adenovirus by Passive Mass Transfer in Cell Culture Simulated in a Computer Model

Activation of conventional kinesin motors in clusters by shaw voltage-gated potassium channels

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