Pseudorabies virus US3 triggers RhoA phosphorylation to reorganize the actin cytoskeleton

Jacob, Thary; Broeke, Céline Van den; Waesberghe, Cliff Van; Troys, Leen Van; Favoreel, Herman

doi:10.1099/vir.0.000152

Cited by 21 publications

(23 citation statements)

References 44 publications

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“…Like the US3-mediated contribution to epithelial spread, the ability of US3 to drive viral passage across the BM depended at least in part on its ability to modulate Rho GTPase signaling. We reported earlier that US3 triggers the Cdc42/Rac1 branch of Rho GTPase signaling by activation of group I PAK and at the same time suppresses RhoA signaling in epithelial cells (14,15). Suppressing US3-mediated activation of PAK reduced the invasive capacity of WT PRV, whereas mimicking US3-mediated inhibition of RhoA increased BM passage of ⌬US3 PRV.…”

Section: Discussionmentioning

confidence: 99%

“…One explanation may be that the inhibitors used do not completely inhibit/mimic the effects of US3. Indeed, US3 activates PAK and at the same time suppresses RhoA activity (15). IPA3 only blocks the ability of US3 to activate PAK, and CPC3 only mimics the ability of US3 to suppress RhoA activity.…”

Section: Discussionmentioning

confidence: 99%

“…US3 has been reported to activate group I PAK signaling (14) and to inhibit RhoA signaling (15). To investigate whether these signaling pathways contribute to the observed effects of US3 in viral spread and invasion in mucosa explants, we used drugs that specifically target group I PAK and RhoA signaling.…”

Section: Us3-mediated Viral Passage Across the Bm Depends On Rhomentioning

confidence: 99%

“…PRV US3 activates the Cdc42/Rac1 branch of Rho GTPase signaling by activating the Cdc42/Rac1 effector group I p21-activated kinases (PAK) (14) and at the same time suppresses RhoA signaling by triggering RhoA phosphorylation (15). This modulation of Rho GTPase signaling leads to profound rearrangements of the actin cytoskeleton in cell culture and is associated with enhanced viral cell-to-cell spread in epithelial cell cultures (14)(15)(16).…”

Section: Importancementioning

confidence: 99%

“…IPA3 is a specific inhibitor of group I PAK (25) and thereby counteracts US3-mediated activation of group I PAK (14). CPC3 is a cell-permeable derivative of Clostridium botulinum coenzyme 3 that inhibits RhoA (29), thereby mimicking the ability of US3 to suppress RhoA signaling (15). CPC3 could be used in 24-h infection assays (not in 48-h infection assays since it caused mild toxicity at that time point), whereas IPA3 did not cause any toxicity and could be used in 48-h assays.…”

Section: Us3-mediated Viral Passage Across the Bm Depends On Rhomentioning

confidence: 99%

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The US3 Protein of Pseudorabies Virus Drives Viral Passage across the Basement Membrane in Porcine Respiratory Mucosa Explants

Lamote

Glorieux

Nauwynck

et al. 2016

J Virol

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Passage of the basement membrane (BM), which forms a barrier between the epithelium and the underlying lamina propria, represents an important step in the early pathogenesis of different alphaherpesviruses. Rho GTPase signaling plays an important role in transmigration of cells across the BM during physiological and pathological processes. We reported earlier that the US3 protein kinase of the alphaherpesvirus pseudorabies virus (PRV) interferes with Rho GTPase signaling and causes a reorganization of the host cell cytoskeleton, which as a consequence, enhances viral cell-to-cell spread in epithelial cell cultures. Here, using an ex vivo system of porcine nasal respiratory mucosa explants that allows to study PRV invasion through the BM, we found that a PRV strain that lacks US3 expression (⌬US3 PRV) showed a reduced spread in mucosal epithelium and was virtually unable to breach the BM, in contrast to isogenic wild-type (WT) or US3 rescue PRV strains. Interestingly, addition of IPA3, an inhibitor of p21-activated kinases that blocks the effects of US3 on the cytoskeleton, suppressed the ability of WT PRV to spread across the BM. In addition, artificial suppression of RhoA signaling using CPC3 (cell-permeable C3 transferase) to mimic the effects of US3 on Rho GTPase signaling, significantly increased passage of ⌬US3 PRV through the BM, whereas it did not significantly affect BM passage of WT or US3 rescue PRV. In conclusion, these data indicate that US3 plays an important role in PRV mucosal invasion across the BM, which involves its interference with Rho GTPase signaling. This is the first report describing an alphaherpesvirus protein that drives viral BM passage. IMPORTANCEMany viruses, including alphaherpesviruses, primarily replicate in epithelial cells of surface mucosae, such as the respiratory mucosa. Some of these viruses breach the basement membrane underlying these epithelial cells to reach underlying connective tissue and blood vessels and invade the host. Hence, epithelial spread and basement membrane passage represent crucial but still poorly understood early steps in (alphaherpes)virus pathogenesis. Here, using ex vivo porcine respiratory mucosa explants, we show that the conserved US3 protein of the porcine alphaherpesvirus pseudorabies virus (PRV) is critical for passage of PRV across the basement membrane and contributes to efficient viral epithelial spread. In addition, we show that US3-mediated viral epithelial spread and passage across the basement membrane depend at least in part on the ability of this viral protein to modulate cellular Rho GTPase signaling. This is the first report that identifies an alphaherpesvirus protein that drives viral basement membrane passage. P seudorabies virus (PRV) is a porcine alphaherpesvirus that is related to other animal alphaherpesviruses, like bovine herpesvirus 1 (BHV1) and equine herpesvirus 1 (EHV1), and the human alphaherpesviruses herpes simplex virus (HSV) and varicella-zoster virus (VZV). Primary replication of many alphaherpesviruses, inc...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Us3-mediated Viral Passage Across the Bm Depends On Rhomentioning

confidence: 99%

Section: Importancementioning

confidence: 99%

Section: Us3-mediated Viral Passage Across the Bm Depends On Rhomentioning

confidence: 99%

See 3 more Smart Citations

The US3 Protein of Pseudorabies Virus Drives Viral Passage across the Basement Membrane in Porcine Respiratory Mucosa Explants

Lamote

Glorieux

Nauwynck

et al. 2016

J Virol

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Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy

Raghavan

Rao

Neužil

et al. 2021

Cell. Mol. Life Sci.

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Tunnelling nanotubes (TNTs) are an emerging route of long-range intercellular communication that mediate cell-to-cell exchange of cargo and organelles and contribute to maintaining cellular homeostasis by balancing diverse cellular stresses. Besides their role in intercellular communication, TNTs are implicated in several ways in health and disease. Transfer of pathogenic molecules or structures via TNTs can promote the progression of neurodegenerative diseases, cancer malignancy, and the spread of viral infection. Additionally, TNTs contribute to acquiring resistance to cancer therapy, probably via their ability to rescue cells by ameliorating various pathological stresses, such as oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, and apoptotic stress. Moreover, mesenchymal stem cells play a crucial role in the rejuvenation of targeted cells with mitochondrial heteroplasmy and oxidative stress by transferring healthy mitochondria through TNTs. Recent research has focussed on uncovering the key regulatory molecules involved in the biogenesis of TNTs. However further work will be required to provide detailed understanding of TNT regulation. In this review, we discuss possible associations with Rho GTPases linked to oxidative stress and apoptotic signals in biogenesis pathways of TNTs and summarize how intercellular trafficking of cargo and organelles, including mitochondria, via TNTs plays a crucial role in disease progression and also in rejuvenation/therapy.

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Amyloid-β induced membrane damage instigates tunneling nanotube-like conduits by p21-activated kinase dependent actin remodulation

Dilna

Deepak

Damodaran

et al. 2021

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Pseudorabies virus US3 triggers RhoA phosphorylation to reorganize the actin cytoskeleton

Cited by 21 publications

References 44 publications

The US3 Protein of Pseudorabies Virus Drives Viral Passage across the Basement Membrane in Porcine Respiratory Mucosa Explants

The US3 Protein of Pseudorabies Virus Drives Viral Passage across the Basement Membrane in Porcine Respiratory Mucosa Explants

Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy

Amyloid-β induced membrane damage instigates tunneling nanotube-like conduits by p21-activated kinase dependent actin remodulation

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