The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons

Diefenbach, Russell J.; Davis, April; Miranda-Saksena, Monica; Fernandez, Marian A.; Kelly, Barbara; Jones, Cheryl; LaVail, Jennifer H.; Xue, Jing; Lai, Joey; Cunningham, Anthony L.

doi:10.1128/jvi.03041-15

Cited by 55 publications

(56 citation statements)

References 53 publications

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“…We compared the presence of Kif5 (kinesin-1) and Kif1a (kinesin-3) in DRM fractions of mock, PRV wild-type, or ΔUs9-infected SCG neurons. Kif1a and Kif5 motors drive anterograde transport of cellular axonal cargoes, and both have been reported to be involved in PRV and HSV-1 anterograde transport [17,35,36]. In wild-type infected samples, we detected an increase in Kif1a in the DRM fractions compared to mock and ΔUs9-infected conditions, but no enrichment of Kif5.…”

Section: Us7-9 Form a Complex That Recruits Kif1amentioning

confidence: 61%

A kinesin-3 recruitment complex facilitates axonal sorting of enveloped alpha herpesvirus capsids

et al. 2020

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Axonal sorting, the controlled passage of specific cargoes from the cell soma into the axon compartment, is critical for establishing and maintaining the polarity of mature neurons. To delineate axonal sorting events, we took advantage of two neuroinvasive alpha-herpesviruses. Human herpes simplex virus 1 (HSV-1) and pseudorabies virus of swine (PRV; suid herpesvirus 1) have evolved as robust cargo of axonal sorting and transport mechanisms. For efficient axonal sorting and subsequent egress from axons and presynaptic termini, progeny capsids depend on three viral membrane proteins (Us7 (gI), Us8 (gE), and Us9), which engage axon-directed kinesin motors. We present evidence that Us7-9 of the veterinary pathogen pseudorabies virus (PRV) form a tripartite complex to recruit Kif1a, a kinesin-3 motor. Based on multi-channel super-resolution and live TIRF microscopy, complex formation and motor recruitment occurs at the trans-Golgi network. Subsequently, progeny virus particles enter axons as enveloped capsids in a transport vesicle. Artificial recruitment of Kif1a using a drug-inducible heterodimerization system was sufficient to rescue axonal sorting and anterograde spread of PRV mutants devoid of Us7-9. Importantly, biophysical evidence suggests that Us9 is able to increase the velocity of Kif1a, a previously undescribed phenomenon. In addition to elucidating mechanisms governing axonal sorting, our results provide further insight into the composition of neuronal transport systems used by alpha-herpesviruses, which will be critical for both inhibiting the spread of infection and the safety of herpesvirus-based oncolytic therapies.

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Section: Us7-9 Form a Complex That Recruits Kif1amentioning

confidence: 61%

A kinesin-3 recruitment complex facilitates axonal sorting of enveloped alpha herpesvirus capsids

et al. 2020

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“…Nevertheless, interpretation of this finding is complicated by the fact that the role of APP in kinesin recruitment is not entirely clear [141,200]. Another possible kinesin-1 receptor is US9p itself, which for HSV-1 has been reported to directly interact with the carboxy-terminal tail of KIF5B [201]. However, if US9p is essential for kinesin-1 recruitment, then loss of US9p should disrupt the rate of trafficking of axonal HSV-1 particles, which does not seem to be the case [161,189].…”

Section: Molecular Roles For Ge/gi and Us9p In Anterograde Transport mentioning

confidence: 99%

Microtubule-Dependent Trafficking of Alphaherpesviruses in the Nervous System: The Ins and Outs

Diwaker

Wilson

2019

Viruses

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The Alphaherpesvirinae include the neurotropic pathogens herpes simplex virus and varicella zoster virus of humans and pseudorabies virus of swine. These viruses establish lifelong latency in the nuclei of peripheral ganglia, but utilize the peripheral tissues those neurons innervate for productive replication, spread, and transmission. Delivery of virions from replicative pools to the sites of latency requires microtubule-directed retrograde axonal transport from the nerve terminus to the cell body of the sensory neuron. As a corollary, during reactivation newly assembled virions must travel along axonal microtubules in the anterograde direction to return to the nerve terminus and infect peripheral tissues, completing the cycle. Neurotropic alphaherpesviruses can therefore exploit neuronal microtubules and motors for long distance axonal transport, and alternate between periods of sustained plus end- and minus end-directed motion at different stages of their infectious cycle. This review summarizes our current understanding of the molecular details by which this is achieved.

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“…We hypothesize that pUS9 may be substituting for viral or cellular protein (perhaps from the TGN or TGN-derived vesicles) only found in the cell body, or alternatively pUS9 is interacting with a growth cone-specific protein not found in the cell body. The next step is to determine which domains in pUS9 facilitate HSV-1 anterograde axonal transport and egress from neurons (28).…”

Section: Figmentioning

confidence: 99%

Dual Role of Herpes Simplex Virus 1 pUS9 in Virus Anterograde Axonal Transport and Final Assembly in Growth Cones in Distal Axons

Miranda-Saksena

Boadle

Diefenbach

et al. 2016

J Virol

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The herpes simplex virus type 1 (HSV-1) envelope protein pUS9 plays an important role in virus anterograde axonal transport and spread from neuronal axons. In this study, we used both confocal microscopy and transmission electron microscopy (TEM) to examine the role of pUS9 in the anterograde transport and assembly of HSV-1 in the distal axon of human and rat dorsal root ganglion (DRG) neurons using US9 deletion (US9 ؊ ), repair (US9R), and wild-type (strain F, 17, and KOS) viruses. Using confocal microscopy and single and trichamber culture systems, we observed a reduction but not complete block in the anterograde axonal transport of capsids to distal axons as well as a marked (ϳ90%) reduction in virus spread from axons to Vero cells with the US9 deletion viruses. Axonal transport of glycoproteins (gC, gD, and gE) was unaffected. Using TEM, there was a marked reduction or absence of enveloped capsids, in varicosities and growth cones, in KOS strain and US9 deletion viruses, respectively. Capsids (40 to 75%) in varicosities and growth cones infected with strain 17, F, and US9 repair viruses were fully enveloped compared to less than 5% of capsids found in distal axons infected with the KOS strain virus (which also lacks pUS9) and still lower (<2%) with the US9 deletion viruses. Hence, there was a secondary defect in virus assembly in distal axons in the absence of pUS9 despite the presence of key envelope proteins. Overall, our study supports a dual role for pUS9, first in anterograde axonal transport and second in virus assembly in growth cones in distal axons. IMPORTANCEHSV-1 has evolved mechanisms for its efficient transport along sensory axons and subsequent spread from axons to epithelial cells after reactivation. In this study, we show that deletion of the envelope protein pUS9 leads to defects in virus transport along axons (partial defect) and in virus assembly and egress from growth cones (marked defect). Virus assembly and exit in the neuronal cell body are not impaired in the absence of pUS9. Thus, our findings indicate that pUS9 contributes to the overall HSV-1 anterograde axonal transport, including a major role in virus assembly at the axon terminus, which is not essential in the neuronal cell body. Overall, our data suggest that the process of virus assembly at the growth cones differs from that in the neuronal cell body and that HSV-1 has evolved different mechanisms for virus assembly and exit from different cellular compartments. Herpes simplex virus 1 (HSV-1) is a neurotropic and neuroinvasive virus that has the ability to infect and remain dormant or latent in neurons of the peripheral nervous system of their human host. After the initial infection of the skin, the virus gains access to the neurons of the dorsal root ganglia via the nerve endings in the innervating skin. Virus reactivation from latency is frequent and results in either asymptomatic virus shedding or recurrent herpes disease (1). Two essential events following reactivation of HSV from latently infected sensory neurons ...

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The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons

Cited by 55 publications

References 53 publications

A kinesin-3 recruitment complex facilitates axonal sorting of enveloped alpha herpesvirus capsids

A kinesin-3 recruitment complex facilitates axonal sorting of enveloped alpha herpesvirus capsids

Microtubule-Dependent Trafficking of Alphaherpesviruses in the Nervous System: The Ins and Outs

Dual Role of Herpes Simplex Virus 1 pUS9 in Virus Anterograde Axonal Transport and Final Assembly in Growth Cones in Distal Axons

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