Association of Ebola Virus Matrix Protein VP40 with Microtubules

Ruthel, Gordon; Demmin, Gretchen L.; Kallstrom, George; Javid, Melodi P.; Badie, Shirin S.; Will, Amy B.; Nelle, Timothy D.; Schokman, Rowena D; Nguyen, Tam Luong; Carra, John H.; Bavari, Sina; Aman, M. Javad

doi:10.1128/jvi.79.8.4709-4719.2005

Cited by 72 publications

(60 citation statements)

References 63 publications

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“…Nef protein in HIV virions functions to allow the viral genome to penetrate the cortical actin network beneath the cytoplasmic membrane (64). The VP40 protein of Ebola virus directly enhances tubulin polymerization, suggesting that microtubules may play an important role in the virus life cycle (65). In the case of Junin virus, cytoskeleton is important for the initiation of the assembly and budding processes at the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

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Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

Huang

Wang

et al. 2011

Journal of Biological Chemistry

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Very little is known about the mechanism of cell entry of avian reovirus (ARV). The aim of this study was to explore the mechanism of ARV entry and subsequent infection. Cholesterol mainly affected the early steps of the ARV life cycle, because the presence of cholesterol before and during viral adsorption greatly blocked ARV infectivity. Although we have demonstrated that ARV facilitating p38 MAPK is beneficial for virus replication, its mechanism remains unknown. Here, we show that ARV-induced phosphorylation of caveolin-1 (Tyr 14 ), dynamin-2 expression, and Rac1 activation through activation of p38 MAPK and Src in the early stage of the virus life cycle is beneficial for virus entry and productive infection. The strong inhibition by dynasore, a specific inhibitor of dynamin-2, and depletion of endogenous caveolin-1 or dynamin-2 by siRNAs as well as the caveolin-1 colocalization study implicate caveolin-1-mediated and dynamin-2-dependent endocytosis as a significant avenue of ARV entry. By means of pharmacological inhibitors, dominant negative mutants, and siRNA of various cellular proteins and signaling molecules, phosphorylation of caveolin-1, dynamin-2 expression, and Rac1 activation were suppressed, suggesting that by orchestrating p38 MAPK, Src, and Rac1 signaling cascade in the target cells, ARV creates an appropriate intracellular environment facilitating virus entry and productive infection. Furthermore, disruption of microtubules, Rab5, or endosome acidification all inhibited ARV infection, suggesting that microtubules and small GTPase Rab5, which regulate transport to early endosome, are crucial for survival of ARV and that exposure of the virus to acidic pH is required for productive infection.

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Section: Discussionmentioning

confidence: 99%

“…Modulation of cytoskeleton organization is important for efficient replication of several viruses (63)(64)(65). Nef protein in HIV virions functions to allow the viral genome to penetrate the cortical actin network beneath the cytoplasmic membrane (64).…”

Section: Discussionmentioning

confidence: 99%

Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

Huang

Wang

et al. 2011

Journal of Biological Chemistry

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“…Oligomers of VP40 associate with microtubules, suggesting that VP40 traffics along microtubules to lipid rafts where assembly occurs [18][19][20][21]. VP40 alone is sufficient to drive viruslike particle (VLP) budding from the rafts, although addition of NP, VP24 and GP facilitates more efficient virion budding [22].…”

Section: Biology Of Filovirus Infectionsmentioning

confidence: 99%

“…Within the nucleocapsid of each virion, a single copy of the viral genome is associated with the nucleoprotein (NP), virion protein (VP)30 and VP35 (FIGURE 1B). The nucleocapsid is enclosed within a host-derived lipid bilayer containing the viral glycoprotein (GP) and matrix proteins VP24 and VP40 [13][14][15][16][17].Oligomers of VP40 associate with microtubules, suggesting that VP40 traffics along microtubules to lipid rafts where assembly occurs [18][19][20][21]. VP40 alone is sufficient to drive viruslike particle (VLP) budding from the rafts, although addition of NP, VP24 and GP facilitates more efficient virion budding [22].…”

mentioning

confidence: 99%

Filovirus-like particles as vaccines and discovery tools

Warfield

Swenson

Demmin

et al. 2005

Expert Review of Vaccines

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Ebola and Marburg viruses are members of the family Filoviridae, which cause severe hemorrhagic fevers in humans. Filovirus outbreaks have been sporadic, with mortality rates currently ranging from 30 to 90%. Unfortunately, there is no efficacious human therapy or vaccine available to treat disease caused by either Ebola or Marburg virus infection. Expression of the filovirus matrix protein, VP40, is sufficient to drive spontaneous production and release of virus-like particles (VLPs) that resemble the distinctively filamentous infectious virions. The addition of other filovirus proteins, including virion proteins (VP)24, 30 and 35 and glycoprotein, increases the efficiency of VLP production and results in particles containing multiple filovirus antigens. Vaccination with Ebola or Marburg VLPs containing glycoprotein and VP40 completely protects rodents from lethal challenge with the homologous virus. These candidate vaccines are currently being tested for immunogenicity and efficacy in nonhuman primates. Furthermore, the Ebola and Marburg VLPs are being used as a surrogate model to further understand the filovirus life cycle, with the goal of developing rationally designed vaccines and therapeutics. Thus, in addition to their use as a vaccine, VLPs are currently being used as tools to learn lessons about filovirus pathogenesis, immunology, replication and assembly requirements.Expert Rev. Vaccines 4(3), 429-440 (2005) Ebola (EBOV) and Marburg (MARV) viruses are the only members of the family Filoviridae, and were named according to their filamentous shape. EBOV and MARV cause acute and rapidly progressive hemorrhagic fever with mortality rates in humans of up to 90% [1,2]. The reservoir for filoviruses is unknown, although the consumption of monkey meat is often associated with onset of disease. Animals ranging from insects to mammals have been analyzed in the hopes of identifying a carrier, but to no avail [3]. After exposure, the onset of clinical symptoms can be as short as 2 days and as long as 21, although most infected humans and nonhuman primates die within 7-10 days of exposure [4]. In addition to hemorrhage and bleeding, other symptoms of filovirus infection include fever, headache, generalized myalgia, prostration, conjunctivitis, rash, lymphadenopathy, pharyngitis and edema [5].Filoviruses are considered serious public health threats, and are classified as biosafety level (BSL)-4 agents and Category A biothreat agents by the US Centers for Disease Control and Prevention [6,101]. Features that characterize filoviruses as a significant global health risk include high morbidity and mortality rates, potential for person-to-person transmission, relative stability in the environment, and feasibility of large-scale production. Additionally, the filoviruses have a low infectious dose, an extremely rapid rate of replication and can be easily transmitted, including via aerosols [4,7,8]. Bolstering the fear of their use as bioterrorism agents, several hemorrhagic fever viruses have a history of state-sponsor...

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“…However, the underlying mechanisms by which many viruses remodel host MT networks and potential roles for MAPs still remain relatively poorly understood. Recent work showed that adenovirus, African swine fever virus (ASFV), influenza A virus, reoviruses, HSV-1, HIV-1, and Ebola virus all induce MT stabilization, often observed with concomitant posttranslational modifications such as acetylation and detyrosination in host cells (90)(91)(92)(93)(94)(95)(96). Specifically, HSV-1 is thought to promote both its trafficking to the nucleus and its egress by multiple mechanisms, including the stabilization and hyper acetylation of MTs by the tegument protein VP22 (94) and viral kinase Us2 (97), binding of the molecular chaperone Hsp90 (98), disruption of the centrosomal nature of the MT-organizing center (MTOC) and its transfer to the trans-Golgi network (97,99,100).…”

Section: Maps Mediate Virus-induced Microtubule Stabilizationmentioning

confidence: 99%

Role of non-motile microtubule-associated proteins in virus trafficking

Portilho

Persson²,

Arhel

2016

Biomolecular Concepts

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Viruses are entirely dependent on their ability to infect a host cell in order to replicate. To reach their site of replication as rapidly and efficiently as possible following cell entry, many have evolved elaborate mechanisms to hijack the cellular transport machinery to propel themselves across the cytoplasm. Long-range movements have been shown to involve motor proteins along microtubules (MTs) and direct interactions between viral proteins and dynein and/or kinesin motors have been well described. Although less well-characterized, it is also becoming increasingly clear that non-motile microtubule-associated proteins (MAPs), including structural MAPs of the MAP1 and MAP2 families, and microtubule plus-end tracking proteins (+ TIPs), can also promote viral trafficking in infected cells, by mediating interaction of viruses with filaments and/or motor proteins, and modulating filament stability. Here we review our current knowledge on nonmotile MAPs, their role in the regulation of cytoskeletal dynamics and in viral trafficking during the early steps of infection.

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Association of Ebola Virus Matrix Protein VP40 with Microtubules

Cited by 72 publications

References 63 publications

Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

Filovirus-like particles as vaccines and discovery tools

Role of non-motile microtubule-associated proteins in virus trafficking

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