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1701. Far away from the lamppost

Title Tesim:
Far away from the lamppost
Creator:
Johnson, G.L., McManus, M.T., Ma’ayan, A., Oprea, T.I., Jan, L., Sklar, L.A., Schürer, S., Roth, B.L., and Shoichet, B.K.
Date of publication:
2018
Abstract Tesim:
[No abstract available]
Resource type:
Article
Affiliation Label Tesim:
Department of Pharmacology
DOI:
https://doi.org/10.17615/129j-jj27
Identifier:
https://dx.doi.org/10.1371/journal.pbio.3000067 and PMID 30532236
ISSN:
1544-9173
Journal Issue:
12
Journal Title:
PLoS Biology
Journal Volume:
16
Language Label:
English
ORCID:
Other Affiliation:
, University of California–San Francisco, Icahn School of Medicine at Mount Sinai, University of New Mexico School of Medicine, University of Miami, Miami, and University of California San Francisco
Person:
Johnson, G.L., McManus, M.T., Ma’ayan, A., Oprea, T.I., Jan, L., Sklar, L.A., Schürer, S., Roth, B.L., and Shoichet, B.K.
Publisher:
Public Library of Science
Rights Statement Label:
In Copyright
Source:
sx61ds342 and bryan_roth_34

1702. An African-specific haplotype in MRGPRX4 is associated with menthol cigarette smoking

Title Tesim:
An African-specific haplotype in MRGPRX4 is associated with menthol cigarette smoking
Creator:
Kozlitina, J., Barik, A., Risso, D., Pagani, L., Roth, B., Luiselli, D., Olsen, R.H.J., Wooding, S., Frigerio-Domingues, C., Sainz, E., Kirchner, T., Niaura, R., Lansu, K., and Drayna, D.
Date of publication:
2019
Abstract Tesim:
In the U.S., more than 80% of African-American smokers use mentholated cigarettes, compared to less than 30% of Caucasian smokers. The reasons for these differences are not well understood. To determine if genetic variation contributes to mentholated cigarette smoking, we performed an exome-wide association analysis in a multiethnic population-based sample from Dallas, TX (N = 561). Findings were replicated in an independent cohort of African Americans from Washington, DC (N = 741). We identified a haplotype of MRGPRX4 (composed of rs7102322[G], encoding N245S, and rs61733596[G], T43T), that was associated with a 5-to-8 fold increase in the odds of menthol cigarette smoking. The variants are present solely in persons of African ancestry. Functional studies indicated that the variant G protein-coupled receptor encoded by MRGPRX4 displays reduced agonism in both arrestin-based and G protein-based assays, and alteration of agonism by menthol. These data indicate that genetic variation in MRGPRX4 contributes to inter-individual and inter-ethnic differences in the preference for mentholated cigarettes, and that the existence of genetic factors predisposing vulnerable populations to mentholated cigarette smoking can inform tobacco control and public health policies.
Resource type:
Article
Affiliation Label Tesim:
Division of Chemical Biology and Medicinal Chemistry
DOI:
https://doi.org/10.17615/yfz3-kx61
Identifier:
https://dx.doi.org/10.1371/journal.pgen.1007916 and PMID 30768591
ISSN:
1553-7390
Journal Issue:
2
Journal Title:
PLoS Genetics
Journal Volume:
15
Language Label:
English
License Label:
Public Domain Mark 1.0
ORCID:
Other Affiliation:
University of Texas Southwestern Medical Center, National Institutes of Health, University of Tartu, , University of Bologna, University of California, Merced, and New York University
Person:
Kozlitina, J., Barik, A., Risso, D., Pagani, L., Roth, B., Luiselli, D., Olsen, R.H.J., Wooding, S., Frigerio-Domingues, C., Sainz, E., Kirchner, T., Niaura, R., Lansu, K., and Drayna, D.
Publisher:
Public Library of Science
Rights Statement Label:
In Copyright
Source:
gm80j1952 and bryan_roth_19

1703. Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides

Title Tesim:
Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides
Creator:
Kashlev, M., Feng, J.Y., Kireeva, M.L., Barauskus, O., Sharma, S.D., Gnatt, A., Smidansky, E.D., Peterson, B.R., Perry, J., Tian, Y., Park, Y., Ray, A.S., Babusis, D., Zhong, W., Xu, Y., Vela, J.E., Cho, A., Cameron, C.E., and Arnold, J.J.
Date of publication:
2012
Abstract Tesim:
Ribonucleoside analogues have potential utility as anti-viral, -parasitic, -bacterial and -cancer agents. However, their clinical applications have been limited by off target effects. Development of antiviral ribonucleosides for treatment of hepatitis C virus (HCV) infection has been hampered by appearance of toxicity during clinical trials that evaded detection during preclinical studies. It is well established that the human mitochondrial DNA polymerase is an off target for deoxyribonucleoside reverse transcriptase inhibitors. Here we test the hypothesis that triphosphorylated metabolites of therapeutic ribonucleoside analogues are substrates for cellular RNA polymerases. We have used ribonucleoside analogues with activity against HCV as model compounds for therapeutic ribonucleosides. We have included ribonucleoside analogues containing 2′-C-methyl, 4′-methyl and 4′-azido substituents that are non-obligate chain terminators of the HCV RNA polymerase. We show that all of the anti-HCV ribonucleoside analogues are substrates for human mitochondrial RNA polymerase (POLRMT) and eukaryotic core RNA polymerase II (Pol II) in vitro. Unexpectedly, analogues containing 2′-C-methyl, 4′-methyl and 4′-azido substituents were inhibitors of POLRMT and Pol II. Importantly, the proofreading activity of TFIIS was capable of excising these analogues from Pol II transcripts. Evaluation of transcription in cells confirmed sensitivity of POLRMT to antiviral ribonucleosides, while Pol II remained predominantly refractory. We introduce a parameter termed the mitovir (mitochondrial dysfunction caused by antiviral ribonucleoside) score that can be readily obtained during preclinical studies that quantifies the mitochondrial toxicity potential of compounds. We suggest the possibility that patients exhibiting adverse effects during clinical trials may be more susceptible to damage by nucleoside analogs because of defects in mitochondrial or nuclear transcription. The paradigm reported here should facilitate development of ribonucleosides with a lower potential for toxicity.
Resource type:
Article
Affiliation Label Tesim:
Department of Microbiology and Immunology
DOI:
https://doi.org/10.17615/qddt-q492
Identifier:
PMID 23166498 and https://dx.doi.org/10.1371/journal.ppat.1003030
ISSN:
1553-7366
Journal Issue:
11
Journal Title:
PLoS Pathogens
Journal Volume:
8
Language Label:
English
ORCID:
Other Affiliation:
Frederick National Laboratory for Cancer Research, Gilead Sciences, Inc., The Pennsylvania State University, University of Maryland School of Medicine, and The University of Kansas
Person:
Kashlev, M., Feng, J.Y., Kireeva, M.L., Barauskus, O., Sharma, S.D., Gnatt, A., Smidansky, E.D., Peterson, B.R., Perry, J., Tian, Y., Park, Y., Ray, A.S., Babusis, D., Zhong, W., Xu, Y., Vela, J.E., Cho, A., Cameron, C.E., and Arnold, J.J.
Rights Statement Label:
In Copyright
Source:
craig_cameron_31 and s4655p49t

1704. The 3′ untranslated regions of influenza genomic sequences are 5′PPP-independent ligands for RIG-i

Title Tesim:
The 3′ untranslated regions of influenza genomic sequences are 5′PPP-independent ligands for RIG-i
Creator:
Sharma, S.D., Wiens, M.E., Pohl, J., Stuchlik, O., Gangappa, S., Bowzard, J.B., Katz, J.M., Ranjan, P., Sambhara, S., Fujita, T., Cameron, C.E., Donis, R.O., and Davis, W.G.
Date of publication:
2012
Abstract Tesim:
Retinoic acid inducible gene-I (RIG-I) is a key regulator of antiviral immunity. RIG-I is generally thought to be activated by ssRNA species containing a 5′-triphosphate (PPP) group or by unphosphorylated dsRNA up to ~300 bp in length. However, it is not yet clear how changes in the length, nucleotide sequence, secondary structure, and 5′ end modification affect the abilities of these ligands to bind and activate RIG-I. To further investigate these parameters in the context of naturally occurring ligands, we examined RNA sequences derived from the 5′ and 3′ untranslated regions (UTR) of the influenza virus NS1 gene segment. As expected, RIG-I-dependent interferon-β (IFN-β) induction by sequences from the 5′ UTR of the influenza cRNA or its complement (26 nt in length) required the presence of a 5′PPP group. In contrast, activation of RIG-I by the 3′ UTR cRNA sequence or its complement (172 nt) exhibited only a partial 5′PPP-dependence, as capping the 5′ end or treatment with CIP showed a modest reduction in RIG-I activation. Furthermore, induction of IFN-β by a smaller, U/A-rich region within the 3′ UTR was completely 5′PPP-independent. Our findings demonstrated that RNA sequence, length, and secondary structure all contributed to whether or not the 5′PPP moiety is needed for interferon induction by RIG-I.
Resource type:
Article
Affiliation Label Tesim:
Department of Microbiology and Immunology
DOI:
https://doi.org/10.17615/aedr-9c88
Identifier:
PMID 22438882 and https://dx.doi.org/10.1371/journal.pone.0032661
ISSN:
1932-6203
Journal Issue:
3
Journal Title:
PLoS ONE
Journal Volume:
7
Language Label:
English
ORCID:
Other Affiliation:
Pennsylvania State University, Centers for Disease Control and Prevention, and Kyoto University
Person:
Sharma, S.D., Wiens, M.E., Pohl, J., Stuchlik, O., Gangappa, S., Bowzard, J.B., Katz, J.M., Ranjan, P., Sambhara, S., Fujita, T., Cameron, C.E., Donis, R.O., and Davis, W.G.
Rights Statement Label:
In Copyright
Source:
pr76f874f and craig_cameron_30

1705. Native Tertiary Structure and Nucleoside Modifications Suppress tRNA's Intrinsic Ability to Activate the Innate Immune Sensor PKR

Title Tesim:
Native Tertiary Structure and Nucleoside Modifications Suppress tRNA's Intrinsic Ability to Activate the Innate Immune Sensor PKR
Creator:
Cameron, C.E., Spremulli, L.L., Ghosh, S.K.B., Bevilacqua, P.C., Nallagatla, S.R., Sharma, S.D., and Jones, C.N.
Date of publication:
2013
Abstract Tesim:
Interferon inducible protein kinase PKR is an essential component of innate immunity. It is activated by long stretches of dsRNA and provides the first line of host defense against pathogens by inhibiting translation initiation in the infected cell. Many cellular and viral transcripts contain nucleoside modifications and/or tertiary structure that could affect PKR activation. We have previously demonstrated that a 5′-end triphosphate-a signature of certain viral and bacterial transcripts-confers the ability of relatively unstructured model RNA transcripts to activate PKR to inhibit translation, and that this activation is abrogated by certain modifications present in cellular RNAs. In order to understand the biological implications of native RNA tertiary structure and nucleoside modifications on PKR activation, we study here the heavily modified cellular tRNAs and the unmodified or the lightly modified mitochondrial tRNAs (mt-tRNA). We find that both a T7 transcript of yeast tRNAPhe and natively extracted total bovine liver mt-tRNA activate PKR in vitro, whereas native E. coli, bovine liver, yeast, and wheat tRNAPhe do not, nor do a variety of base- or sugar-modified T7 transcripts. These results are further supported by activation of PKR by a natively folded T7 transcript of tRNAPhe in vivo supporting the importance of tRNA modification in suppressing PKR activation in cells. We also examine PKR activation by a T7 transcript of the A14G pathogenic mutant of mt-tRNALeu, which is known to dimerize, and find that the misfolded dimeric form activates PKR in vitro while the monomeric form does not. Overall, the in vitro and in vivo findings herein indicate that tRNAs have an intrinsic ability to activate PKR and that nucleoside modifications and native RNA tertiary folding may function, at least in part, to suppress such activation, thus serving to distinguish self and non-self tRNA in innate immunity.
Resource type:
Article
Affiliation Label Tesim:
Department of Microbiology and Immunology and Department of Chemistry
DOI:
https://doi.org/10.17615/khc6-xc60
Identifier:
PMID 23483938 and https://dx.doi.org/10.1371/journal.pone.0057905
ISSN:
1932-6203
Journal Issue:
3
Journal Title:
PLoS ONE
Journal Volume:
8
Language Label:
English
ORCID:
Other Affiliation:
The Pennsylvania State University and
Person:
Cameron, C.E., Spremulli, L.L., Ghosh, S.K.B., Bevilacqua, P.C., Nallagatla, S.R., Sharma, S.D., and Jones, C.N.
Rights Statement Label:
In Copyright
Source:
craig_cameron_27 and ft848x36t

1706. Interferon and Ribavirin Combination Treatment Synergistically Inhibit HCV Internal Ribosome Entry Site Mediated Translation at the Level of Polyribosome Formation

Title Tesim:
Interferon and Ribavirin Combination Treatment Synergistically Inhibit HCV Internal Ribosome Entry Site Mediated Translation at the Level of Polyribosome Formation
Creator:
Chandra, P.K., Zhang, H., Hazari, S., Cameron, C.E., Dash, S., Chandra, S., Garry, R.F., Datta, S., Huang, Z., Balart, L.A., Panigrahi, R., and Kurt, R.
Date of publication:
2013
Abstract Tesim:
Purpose:Although chronic hepatitis C virus (HCV) infection has been treated with the combination of interferon alpha (IFN-α) and ribavirin (RBV) for over a decade, the mechanism of antiviral synergy is not well understood. We aimed to determine the synergistic antiviral mechanisms of IFN-α and RBV combination treatment using HCV cell culture.Methods:The antiviral efficacy of IFN-α, RBV alone and in combination was quantitatively measured using HCV infected and replicon cell culture. Direct antiviral activity of these two drugs at the level of HCV internal ribosome entry site (IRES) mediated translation in Huh-7 cell culture was investigated. The synergistic antiviral effect of IFN-α and RBV combination treatment was verified using both the CalcuSyn Software and MacSynergy Software.Results:RBV combination with IFN-α efficiently inhibits HCV replication cell culture. Our results demonstrate that IFN-α, interferon lambda (IFN-λ) and RBV each inhibit the expression of HCV IRES-GFP and that they have a minimal effect on the expression of GFP in which the translation is not IRES dependent. The combination treatments of RBV along with IFN-α or IFN-λ were highly synergistic with combination indexes <1. We show that IFN-α treatment induce levels of PKR and eIF2α phosphorylation that prevented ribosome loading of the HCV IRES-GFP mRNA. Silencing of PKR expression in Huh-7 cells prevented the inhibitory effect of IFN-α on HCV IRES-GFP expression. RBV also blocked polyribosome loading of HCV-IRES mRNA through the inhibition of cellular IMPDH activity, and induced PKR and eIF2α phosphorylation. Knockdown of PKR or IMPDH prevented RBV induced HCV IRES-GFP translation.Conclusions:We demonstrated both IFN-α and RBV inhibit HCV IRES through prevention of polyribosome formation. The combination of IFN-α and RBV treatment synergistically inhibits HCV IRES translation via using two different mechanisms involving PKR activation and depletion of intracellular guanosine pool through inhibition of IMPDH.
Resource type:
Article
Affiliation Label Tesim:
Department of Microbiology and Immunology
DOI:
https://doi.org/10.17615/0dex-c396
Identifier:
https://dx.doi.org/10.1371/journal.pone.0072791 and PMID 24009705
ISSN:
1932-6203
Journal Issue:
8
Journal Title:
PLoS ONE
Journal Volume:
8
Language Label:
English
ORCID:
Other Affiliation:
Tulane University School of Medicine, Penn State University, and Southern Research Institute
Person:
Chandra, P.K., Zhang, H., Hazari, S., Cameron, C.E., Dash, S., Chandra, S., Garry, R.F., Datta, S., Huang, Z., Balart, L.A., Panigrahi, R., and Kurt, R.
Rights Statement Label:
In Copyright
Source:
craig_cameron_26 and gf06g837x

1707. Cytoplasmic Viral RNA-Dependent RNA Polymerase Disrupts the Intracellular Splicing Machinery by Entering the Nucleus and Interfering with Prp8

Title Tesim:
Cytoplasmic Viral RNA-Dependent RNA Polymerase Disrupts the Intracellular Splicing Machinery by Entering the Nucleus and Interfering with Prp8
Creator:
Huang, P.-N., Liu, Y.-C., Huang, Y., Arnold, J.J., Liu, H., Chen, S.-J., Cameron, C.E., Shih, S.-R., Lin, J.-Y., Wang, R.Y.-L., and Kuo, R.-L.
Date of publication:
2014
Abstract Tesim:
The primary role of cytoplasmic viral RNA-dependent RNA polymerase (RdRp) is viral genome replication in the cellular cytoplasm. However, picornaviral RdRp denoted 3D polymerase (3Dpol) also enters the host nucleus, where its function remains unclear. In this study, we describe a novel mechanism of viral attack in which 3Dpol enters the nucleus through the nuclear localization signal (NLS) and targets the pre-mRNA processing factor 8 (Prp8) to block pre-mRNA splicing and mRNA synthesis. The fingers domain of 3Dpol associates with the C-terminal region of Prp8, which contains the Jab1/MPN domain, and interferes in the second catalytic step, resulting in the accumulation of the lariat form of the splicing intermediate. Endogenous pre-mRNAs trapped by the Prp8-3Dpol complex in enterovirus-infected cells were identified and classed into groups associated with cell growth, proliferation, and differentiation. Our results suggest that picornaviral RdRp disrupts pre-mRNA splicing processes, that differs from viral protease shutting off cellular transcription and translation which contributes to the pathogenesis of viral infection. © 2014 Liu et al.
Resource type:
Article
Affiliation Label Tesim:
Department of Microbiology and Immunology
DOI:
https://doi.org/10.17615/r9bm-wd42
Identifier:
https://dx.doi.org/10.1371/journal.ppat.1004199 and PMID 24968230
ISSN:
1553-7366
Journal Issue:
6
Journal Title:
PLoS Pathogens
Journal Volume:
10
Language Label:
English
ORCID:
Other Affiliation:
Chang Gung University, Pennsylvania State University, and Taipei Medical University
Person:
Huang, P.-N., Liu, Y.-C., Huang, Y., Arnold, J.J., Liu, H., Chen, S.-J., Cameron, C.E., Shih, S.-R., Lin, J.-Y., Wang, R.Y.-L., and Kuo, R.-L.
Publisher:
Public Library of Science
Rights Statement Label:
In Copyright
Source:
craig_cameron_24 and 8p58pk67m

1708. Sequence-Specific Fidelity Alterations Associated with West Nile Virus Attenuation in Mosquitoes

Title Tesim:
Sequence-Specific Fidelity Alterations Associated with West Nile Virus Attenuation in Mosquitoes
Creator:
Kramer, L.D., Moustafa, I.M., Ciota, A.T., Lugo, A.J., Van Slyke, G.A., Cameron, C.E., Arnold, J.J., and Griesemer, S.B.
Date of publication:
2015
Abstract Tesim:
High rates of error-prone replication result in the rapid accumulation of genetic diversity of RNA viruses. Recent studies suggest that mutation rates are selected for optimal viral fitness and that modest variations in replicase fidelity may be associated with viral attenuation. Arthropod-borne viruses (arboviruses) are unique in their requirement for host cycling and may necessitate substantial genetic and phenotypic plasticity. In order to more thoroughly investigate the correlates, mechanisms and consequences of arbovirus fidelity, we selected fidelity variants of West Nile virus (WNV; Flaviviridae, Flavivirus) utilizing selection in the presence of a mutagen. We identified two mutations in the WNV RNA-dependent RNA polymerase associated with increased fidelity, V793I and G806R, and a single mutation in the WNV methyltransferase, T248I, associated with decreased fidelity. Both deep-sequencing and in vitro biochemical assays confirmed strain-specific differences in both fidelity and mutational bias. WNV fidelity variants demonstrated host-specific alterations to replicative fitness in vitro, with modest attenuation in mosquito but not vertebrate cell culture. Experimental infections of colonized and field populations of Cx. quinquefaciatus demonstrated that WNV fidelity alterations are associated with a significantly impaired capacity to establish viable infections in mosquitoes. Taken together, these studies (i) demonstrate the importance of allosteric interactions in regulating mutation rates, (ii) establish that mutational spectra can be both sequence and strain-dependent, and (iii) display the profound phenotypic consequences associated with altered replication complex function of flaviviruses.
Resource type:
Article
Affiliation Label Tesim:
Department of Microbiology and Immunology
DOI:
https://doi.org/10.17615/pzcn-5j70
Identifier:
https://dx.doi.org/10.1371/journal.ppat.1005009 and PMID 26114757
ISSN:
1553-7366
Journal Issue:
6
Journal Title:
PLoS Pathogens
Journal Volume:
11
Language Label:
English
ORCID:
Other Affiliation:
New York State Department of Health and The Pennsylvania State University
Person:
Kramer, L.D., Moustafa, I.M., Ciota, A.T., Lugo, A.J., Van Slyke, G.A., Cameron, C.E., Arnold, J.J., and Griesemer, S.B.
Publisher:
Public Library of Science
Rights Statement Label:
In Copyright
Source:
craig_cameron_18 and rj430962j

1709. The RNA Template Channel of the RNA-Dependent RNA Polymerase as a Target for Development of Antiviral Therapy of Multiple Genera within a Virus Family

Title Tesim:
The RNA Template Channel of the RNA-Dependent RNA Polymerase as a Target for Development of Antiviral Therapy of Multiple Genera within a Virus Family
Creator:
Cameron, C.E., Canard, B., De Clercq, K., Lefebvre, D., Lacroix, C., van Kuppeveld, F.J.M., Selisko, B., Goris, N., Vives-Adrián, L., De Palma, A.M., van der Linden, L., Neyts, J., Pürstinger, G., Lanke, K., Tanchis, F., Arnold, J.J., Boehr, D.D., Verdaguer, N., Liu, X., Ferrer-Orta, C., Ulferts, R., Leyssen, P., and Coutard, B.
Date of publication:
2015
Abstract Tesim:
The genus Enterovirus of the family Picornaviridae contains many important human pathogens (e.g., poliovirus, coxsackievirus, rhinovirus, and enterovirus 71) for which no antiviral drugs are available. The viral RNA-dependent RNA polymerase is an attractive target for antiviral therapy. Nucleoside-based inhibitors have broad-spectrum activity but often exhibit off-target effects. Most non-nucleoside inhibitors (NNIs) target surface cavities, which are structurally more flexible than the nucleotide-binding pocket, and hence have a more narrow spectrum of activity and are more prone to resistance development. Here, we report a novel NNI, GPC-N114 (2,2'-[(4-chloro-1,2-phenylene)bis(oxy)]bis(5-nitro-benzonitrile)) with broad-spectrum activity against enteroviruses and cardioviruses (another genus in the picornavirus family). Surprisingly, coxsackievirus B3 (CVB3) and poliovirus displayed a high genetic barrier to resistance against GPC-N114. By contrast, EMCV, a cardiovirus, rapidly acquired resistance due to mutations in 3Dpol. In vitro polymerase activity assays showed that GPC-N114 i) inhibited the elongation activity of recombinant CVB3 and EMCV 3Dpol, (ii) had reduced activity against EMCV 3Dpol with the resistance mutations, and (iii) was most efficient in inhibiting 3Dpol when added before the RNA template-primer duplex. Elucidation of a crystal structure of the inhibitor bound to CVB3 3Dpol confirmed the RNA-binding channel as the target for GPC-N114. Docking studies of the compound into the crystal structures of the compound-resistant EMCV 3Dpol mutants suggested that the resistant phenotype is due to subtle changes that interfere with the binding of GPC-N114 but not of the RNA template-primer. In conclusion, this study presents the first NNI that targets the RNA template channel of the picornavirus polymerase and identifies a new pocket that can be used for the design of broad-spectrum inhibitors. Moreover, this study provides important new insight into the plasticity of picornavirus polymerases at the template binding site.
Resource type:
Article
Affiliation Label Tesim:
Department of Microbiology and Immunology
DOI:
https://doi.org/10.17615/yjrb-2b19
Identifier:
https://dx.doi.org/10.1371/journal.ppat.1004733 and PMID 25799064
ISSN:
1553-7366
Journal Issue:
3
Journal Title:
PLoS Pathogens
Journal Volume:
11
Language Label:
English
ORCID:
Other Affiliation:
Pennsylvania State University, Aix-Marseille Université & CNRS, Veterinary and Agrochemical Research Centre, University of Leuven, Radboud University Medical Centre, Okapi Sciences NV, Parc Científic de Barcelona, Universität Innsbruck, and Aix-Marseille Université & CNRS
Page End:
23
Page Start:
1
Person:
Cameron, C.E., Canard, B., De Clercq, K., Lefebvre, D., Lacroix, C., van Kuppeveld, F.J.M., Selisko, B., Goris, N., Vives-Adrián, L., De Palma, A.M., van der Linden, L., Neyts, J., Pürstinger, G., Lanke, K., Tanchis, F., Arnold, J.J., Boehr, D.D., Verdaguer, N., Liu, X., Ferrer-Orta, C., Ulferts, R., Leyssen, P., and Coutard, B.
Publisher:
Public Library of Science
Rights Statement Label:
In Copyright
Source:
rn301668f and craig_cameron_17

1710. UGGT1 enhances enterovirus 71 pathogenicity by promoting viral RNA synthesis and viral replication

Title Tesim:
UGGT1 enhances enterovirus 71 pathogenicity by promoting viral RNA synthesis and viral replication
Creator:
Arnold, J.J., Shih, S.-R., Jheng, J.-R., Huang, P.-N., Wang, J.-R., and Cameron, C.E.
Date of publication:
2017
Abstract Tesim:
Positive-strand RNA virus infections can induce the stress-related unfolded protein response (UPR) in host cells. This study found that enterovirus A71 (EVA71) utilizes host UDP-glucose glycoprotein glucosyltransferase 1 (UGGT1), a key endoplasmic reticulum protein (ER) involved in UPR, to enhance viral replication and virulence. EVA71 forms replication complexes (RCs) on cellular membranes that contain a mix of host and viral proteins to facilitate viral replication, but the components and processes involved in the assembly and function of RCs are not fully understood. Using EVA71 as a model, this study found that host UGGT1 and viral 3D polymerase co-precipitate along with other factors on membranous replication complexes to enhance viral replication. Increased UGGT1 levels elevated viral growth rates, while viral pathogenicity was observed to be lower in heterozygous knockout mice (Uggt1 +/- mice). These findings provide important insight on the role of UPR and host UGGT1 in regulating RNA virus replication and pathogenicity.
Resource type:
Article
Affiliation Label Tesim:
Department of Microbiology and Immunology
DOI:
https://doi.org/10.17615/y5kr-2r69
Identifier:
PMID 28545059 and https://dx.doi.org/10.1371/journal.ppat.1006375
ISSN:
1553-7366
Journal Issue:
5
Journal Title:
PLoS Pathogens
Journal Volume:
13
Language Label:
English
ORCID:
Other Affiliation:
Pennsylvania State University, Chang Gung University, and National Cheng Kung University
Person:
Arnold, J.J., Shih, S.-R., Jheng, J.-R., Huang, P.-N., Wang, J.-R., and Cameron, C.E.
Publisher:
Public Library of Science
Rights Statement Label:
In Copyright
Source:
z316q665s and craig_cameron_14