Ebola Virus VP24 Targets a Unique NLS Binding Site on Karyopherin Alpha 5 to Selectively Compete with Nuclear Import of Phosphorylated STAT1

Xü, Wei; Edwards, Megan R.; Borek, Dominika; Feagins, Alicia R.; Mittal, Anuradha; Alinger, Joshua B.; Berry, Kayla N.; Yen, Benjamin; Hamilton, Jennifer; Brett, Tom J.; Pappu, Rohit V.; Leung, Daisy W.; Basler, Christopher F.; Amarasinghe, Gaya K.

doi:10.1016/j.chom.2014.07.008

Cited by 209 publications

(274 citation statements)

References 44 publications

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“…This result suggests that VP24 plays a key role in the different virulence in different outbreaks according to the classification and the different lethality of each subspecies. This discovery is consistent with other medical research that VP24 is the molecular determinant of ebolavirus virulence (Xu, 2014). We suggest that VP24 should be the most important target to block when we develop drugs or vaccines.…”

Section: Ebolavirus Classification Based On Natural Vectorssupporting

confidence: 75%

“…It is also responsible for the NP-NP interaction and replication of the viral genome (Watanabe et al, 2006). Xu (2014) showed that VP24 binds to the karyopherin alpha nuclear transporters and blocks the nuclear accumulation of STAT1, a very important component of the immune system (Xu et al, 2014). An earlier study revealed that VP35 blocks production of interferon, a critical component for immune defense against viruses.…”

Section: Introductionmentioning

confidence: 99%

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Ebolavirus Classification Based on Natural Vectors

Zheng

Yin

Hoang

et al. 2015

DNA and Cell Biology

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According to the WHO, ebolaviruses have resulted in 8818 human deaths in West Africa as of January 2015. To better understand the evolutionary relationship of the ebolaviruses and infer virulence from the relationship, we applied the alignment-free natural vector method to classify the newest ebolaviruses. The dataset includes three new Guinea viruses as well as 99 viruses from Sierra Leone. For the viruses of the family of Filoviridae, both genus label classification and species label classification achieve an accuracy rate of 100%. We represented the relationships among Filoviridae viruses by Unweighted Pair Group Method with Arithmetic Mean (UPGMA) phylogenetic trees and found that the filoviruses can be separated well by three genera. We performed the phylogenetic analysis on the relationship among different species of Ebolavirus by their coding-complete genomes and seven viral protein genes (glycoprotein [GP], nucleoprotein [NP], VP24, VP30, VP35, VP40, and RNA polymerase [L]). The topology of the phylogenetic tree by the viral protein VP24 shows consistency with the variations of virulence of ebolaviruses. The result suggests that VP24 be a pharmaceutical target for treating or preventing ebolaviruses.

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Section: Ebolavirus Classification Based On Natural Vectorssupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Ebolavirus Classification Based on Natural Vectors

Zheng

Yin

Hoang

et al. 2015

DNA and Cell Biology

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“…Ebolavirus proteins contain a significant fraction (20%) of structurally disordered regions, and the fraction of variable positions in these regions is significantly higher (p < 0.01) than in the structurally ordered regions. The 3D structures of globular regions are mostly known (Table S2) [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] except for the N-terminal zinc-finger domain of VP30, the coiled-coil domain of VP35, and protein L. Identification and analysis of structurally characterized homologs allowed us to predict the structure of the zinc-finger domain in VP30, the overall topology of NP, and the structure and catalytic sites for the catalytic domains of protein L.…”

Section: Resultsmentioning

confidence: 99%

Predictive and comparative analysis of Ebolavirus proteins

2015

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Ebolavirus is the pathogen for Ebola Hemorrhagic Fever (EHF). This disease exhibits a high fatality rate and has recently reached a historically epidemic proportion in West Africa. Out of the 5 known Ebolavirus species, only Reston ebolavirus has lost human pathogenicity, while retaining the ability to cause EHF in long-tailed macaque. Significant efforts have been spent to determine the three-dimensional (3D) structures of Ebolavirus proteins, to study their interaction with host proteins, and to identify the functional motifs in these viral proteins. Here, in light of these experimental results, we apply computational analysis to predict the 3D structures and functional sites for Ebolavirus protein domains with unknown structure, including a zinc-finger domain of VP30, the RNA-dependent RNA polymerase catalytic domain and a methyltransferase domain of protein L. In addition, we compare sequences of proteins that interact with Ebolavirus proteins from RESTV-resistant primates with those from RESTV-susceptible monkeys. The host proteins that interact with GP and VP35 show an elevated level of sequence divergence between the RESTV-resistant and RESTV-susceptible species, suggesting that they may be responsible for host specificity. Meanwhile, we detect variable positions in protein sequences that are likely associated with the loss of human pathogenicity in RESTV, map them onto the 3D structures and compare their positions to known functional sites. VP35 and VP30 are significantly enriched in these potential pathogenicity determinants and the clustering of such positions on the surfaces of VP35 and GP suggests possible uncharacterized interaction sites with host proteins that contribute to the virulence of Ebolavirus.

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“…The other EBOV protein that antagonizes the innate immune response, VP24, acts by mechanisms distinct from those of VP35. VP24 interacts with karyopherin ␣ nuclear transporters to prevent translocation of STAT1 to the nucleus (29)(30)(31)(32) and also binds to heterogeneous ribonuclear protein complex C1/C2 (hnRNP C1/ C2), which normally interacts with karyopherin ␣1, and partially alters the nuclear transport of hnRNP C1/C2 (33). The interaction of VP24 with karyopherin ␣1 is completely reversed by the mutation K142A (29).…”

mentioning

confidence: 99%

Different Temporal Effects of Ebola Virus VP35 and VP24 Proteins on Global Gene Expression in Human Dendritic Cells

Ilinykh

Lubaki

Widen

et al. 2015

J Virol

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Ebola virus (EBOV) causes Filoviruses cause a severe hemorrhagic fever in humans and nonhuman primates with a mortality in humans of up to 90% (1). Filoviruses include five species, Zaire ebolavirus, Bundibugyo ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus, and Reston ebolavirus, belonging to the genus Ebolavirus, and a single species, Marburg marburgvirus, belonging to the genus Marburgvirus (2). Filovirus outbreaks occur in Central Africa regularly; in 2012, four filovirus outbreaks occurred in Uganda and the Democratic Republic of the Congo (3), and a new outbreak with a previously unknown clade of Ebola virus (EBOV), which belongs to the species Zaire ebolavirus, started in Guinea in the winter of 2013-2014 (4) and spread to Liberia, Sierra Leone, Nigeria, Senegal, Mali, Spain, the United States, and the United Kingdom (5). Because of the extremely high mortality of the disease caused by filoviruses and the lack of approved vaccine and treatments, work with these viruses is performed under the biosafety level 4 (BSL-4) biocontainment.EBOV causes a severe immunosuppression in both humans and nonhuman primate models, characterized by a deficient T cell response, lymphopenia, and T cell apoptosis, despite the lack of infection of T cells (6)(7)(8)(9)(10)(11)(12). On the other hand, dendritic cells (DC), which are the most effective antigen-presenting cells and are infected by EBOV, do not undergo normal maturation despite the infection (13-15). Because DC play a key role in initiation of the adaptive immune response by processing viral antigens and presenting them to naive lymphocytes, the deficient T cell response may be linked to the deficient and/or aberrant stimulation of T cells by the infected DC.EBOV has two proteins, VP35 and VP24, which antagonize the

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Ebola Virus VP24 Targets a Unique NLS Binding Site on Karyopherin Alpha 5 to Selectively Compete with Nuclear Import of Phosphorylated STAT1

Cited by 209 publications

References 44 publications

Ebolavirus Classification Based on Natural Vectors

Ebolavirus Classification Based on Natural Vectors

Predictive and comparative analysis of Ebolavirus proteins

Different Temporal Effects of Ebola Virus VP35 and VP24 Proteins on Global Gene Expression in Human Dendritic Cells

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