Ebola Virus Glycoprotein Toxicity Is Mediated by a Dynamin-Dependent Protein-Trafficking Pathway

Sullivan, Nancy J.; Peterson, Mary; Yang, Zhi Yong; Kong, Wing Pui; Duckers, Heinricus; Nabel, Elizabeth G.; Nabel, Gary J.

doi:10.1128/jvi.79.1.547-553.2005

Cited by 69 publications

(87 citation statements)

References 20 publications

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“…Several potential mechanisms that contribute to pathogenesis have been reviewed (36). These include viral glycoprotein-mediated cytotoxicity, dysregulation of the coagulation cascade due to the production of tissue factor, and the production of proinflammatory cytokines (10,16,17,51,54,57). General immunosuppression also appears to be a characteristic of EBOV infection (7,46), and inhibition of dendritic cell and macrophage activation are among the possible mechanisms of this suppression (5,18,38).…”

Section: Ebola Virus (Ebov) and Marburg Virus Comprise The Familymentioning

confidence: 99%

Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1

Reid

Valmas

Martinez

et al. 2007

J Virol

227

249

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The Zaire ebolavirus protein VP24 was previously demonstrated to inhibit alpha/beta interferon (IFN-␣/␤)-and IFN-␥-induced nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1) and to inhibit IFN-␣/␤-and IFN-␥-induced gene expression. These properties correlated with the ability of VP24 to interact with the nuclear localization signal receptor for PY-STAT1, karyopherin ␣1. Here, VP24 is demonstrated to interact not only with overexpressed but also with endogenous karyopherin ␣1. Mutational analysis demonstrated that VP24 binds within the PY-STAT1 binding region located in the C terminus of karyopherin ␣1. In addition, VP24 was found to inhibit PY-STAT1 binding to both overexpressed and endogenous karyopherin ␣1. We assessed the binding of both PY-STAT1 and the VP24 proteins from Zaire, mouse-adapted Zaire, and Reston Ebola viruses for interaction with all six members of the human karyopherin ␣ family. We found, in contrast to previous studies, that PY-STAT1 can interact not only with karyopherin ␣1 but also with karyopherins ␣5 and ␣6, which together comprise the NPI-1 subfamily of karyopherin ␣s. Similarly, all three VP24s bound and inhibited PY-STAT1 interaction with karyopherins ␣1, ␣5, and ␣6. Consistent with their ability to inhibit the karyopherin-PY-STAT1 interaction, Zaire, mouse-adapted Zaire, and Reston Ebola virus VP24s displayed similar capacities to inhibit IFN-␤-induced gene expression in human and mouse cells. These findings suggest that VP24 inhibits interaction of PY-STAT1 with karyopherins ␣1, ␣5, or ␣6 by binding within the PY-STAT1 binding region of the karyopherins and that this function is conserved among the VP24 proteins of different Ebola virus species.

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Section: Ebola Virus (Ebov) and Marburg Virus Comprise The Familymentioning

confidence: 99%

Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1

Reid

Valmas

Martinez

et al. 2007

J Virol

227

249

View full text Add to dashboard Cite

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“…The mucin domain of GP causes rounding and detachment of infected cells, resulting from a strong global downregulation of cell surface proteins and a loss of cell adherence, without causing cell death (17,18). Another study described GP as the main viral determinant of vascular cell toxicity and injury (19), which was suggested to be mediated by a dynamin-dependent protein-trafficking pathway (20). The GP-induced cytotoxicity was also shown to be mediated by the ERK mitogen-activated protein kinase pathway (21).…”

mentioning

confidence: 99%

The Lack of Maturation of Ebola Virus-Infected Dendritic Cells Results from the Cooperative Effect of at Least Two Viral Domains

Lubaki

Ilinykh

Pietzsch

et al. 2013

J Virol

127

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dEbola virus (EBOV) infections are characterized by deficient T lymphocyte responses, T lymphocyte apoptosis, and lymphopenia in the absence of direct infection of T lymphocytes. In contrast, dendritic cells (DC) are infected but fail to mature appropriately, thereby impairing the T cell response. We investigated the contributions of EBOV proteins in modulating DC maturation by generating recombinant viruses expressing enhanced green fluorescent protein and carrying mutations affecting several potentially immunomodulating domains. They included envelope glycoprotein (GP) domains, as well as innate response antagonist domains (IRADs) previously identified in the VP24 and VP35 proteins. GP expressed by an unrelated vector, but not the wild-type EBOV, was found to strongly induce DC maturation, and infections with recombinant EBOV carrying mutations disabling GP functional domains did not restore DC maturation. In contrast, each of the viruses carrying mutations disabling any IRAD in VP35 induced a dramatic upregulation of DC maturation markers. This was dependent on infection, but not interaction with GP. Disabling of IRADs also resulted in up to a several hundredfold increase in secretion of cytokines and chemokines. Furthermore, these mutations induced formation of homotypic DC clusters, which represent close correlates of their maturation and presumably facilitate transfer of antigen from migratory DC to lymph node DC. Thus, an individual IRAD is insufficient to suppress DC maturation; rather, the suppression of DC maturation and the "immune paralysis" observed during EBOV infections results from a cooperative effect of two or more individual IRADs.

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“…Cytotoxicity caused by EBOV GP is believed to play an important role in the hemorrhagic manifestations that are widely observed in patients and laboratory-infected monkeys [4,18,20,22]. However, the molecular events that lead to these cytopathic effects during viral infection are poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…EBOV GP plays a key role in the manifestations of EBOV infection, including inflammatory dysregulation, immune suppression and a loss of vascular integrity [4,6,20,22,39]. However, these changes have mainly focused on alterations at the protein level.…”

Section: Differential Mirnas Expression In Ebov Gpexpressing Huvecsmentioning

confidence: 99%

“…In addition, dynamin-dependent protein-trafficking pathway [22] and ERK signaling cascade [23] were also involved in GP-mediated cytotoxicity. Moreover, GP has other functions including induction of anoikis [19], stimulation of cytokines [24] and tissue factors [25,26] secreted from monocytes/macrophages and dendritic cells which induced the endothelial disturbances and coagulation irregularities [18,27,28].…”

mentioning

confidence: 99%

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Hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p inhibitors can reduce the cytotoxicity of Ebola virus glycoprotein in vitro

Sheng

Zhang

Chen

et al. 2014

Sci. China Life Sci.

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Ebola virus (EBOV) causes a highly lethal hemorrhagic fever syndrome in humans and has been associated with mortality rates of up to 91% in Zaire, the most lethal strain. Though the viral envelope glycoprotein (GP) mediates widespread inflammation and cellular damage, these changes have mainly focused on alterations at the protein level, the role of microRNAs (miRNAs) in the molecular pathogenesis underlying this lethal disease is not fully understood. Here, we report that the miRNAs hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p were induced in human umbilical vein endothelial cells (HUVECs) following expression of EBOV GP. Among the proteins encoded by predicted targets of these miRNAs, the adhesion-related molecules tissue factor pathway inhibitor (TFPI), dystroglycan1 (DAG1) and the caspase 8 and FADD-like apoptosis regulator (CFLAR) were significantly downregulated in EBOV GP-expressing HUVECs. Moreover, inhibition of hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p, or overexpression of TFPI, DAG1 and CFLAR rescued the cell viability that was induced by EBOV GP. Our results provide a novel molecular basis for EBOV pathogenesis and may contribute to the development of strategies to protect against future EBOV pandemics. Ebola virus, glycoprotein, microRNAs, cytotoxicity Citation:Sheng MM, Zhong Y, Chen Y, Du JC, Ju XW, Zhao C, Zhang GG, Zhang LF, Liu KT, Yang N, Xie P, Li DS, Zhang MQ, Jiang CY. Hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p inhibitors can reduce the cytotoxicity of Ebola virus glycoprotein in vitro. Sci China Life Sci, 2014, 57: 959 -972,

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Ebola Virus Glycoprotein Toxicity Is Mediated by a Dynamin-Dependent Protein-Trafficking Pathway

Cited by 69 publications

References 20 publications

Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1

Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1

The Lack of Maturation of Ebola Virus-Infected Dendritic Cells Results from the Cooperative Effect of at Least Two Viral Domains

Hsa-miR-1246, hsa-miR-320a and hsa-miR-196b-5p inhibitors can reduce the cytotoxicity of Ebola virus glycoprotein in vitro

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