scholarly journals Faculty Opinions recommendation of Major human cytomegalovirus structural protein pp65 (ppUL83) prevents interferon response factor 3 activation in the interferon response.

2004 ◽  
Author(s):  
Grant McFadden
Keyword(s):  
Human Cytomegalovirus ◽  
Interferon Response ◽  
Response Factor ◽  
Structural Protein

scholarly journals Major Human Cytomegalovirus Structural Protein pp65 (ppUL83) Prevents Interferon Response Factor 3 Activation in the Interferon Response

2004 ◽  
Vol 78 (20) ◽  
pp. 10995-11006 ◽  
Author(s):  
Davide A. Abate ◽  
Shinya Watanabe ◽  
Edward S. Mocarski
Keyword(s):  
Underlying Mechanism ◽  
Nuclear Accumulation ◽  
Interferon Response ◽  
Type I ◽  
Response Factor ◽  
Structural Protein ◽  
Virion Protein ◽  
Virus Binding ◽  
Rapid Induction ◽  
Antiviral Control

ABSTRACT We have identified a cytomegalovirus virion protein capable of modulating the rapid induction of an interferon-like response in cells that follows virus binding and penetration. Functional genomics revealed a role for the major cytomegalovirus structural protein, pp65 (ppUL83), in counteracting this response. The underlying mechanism involves a differential impact of this structural protein on the regulation of interferon response factor 3 (IRF-3). In contrast, NF-κB is activated independent of pp65, and neither STAT1 nor STAT3 becomes activated by either virus. pp65 is sufficient to prevent the activation of IRF-3 when introduced alone into cells. pp65 acts by inhibiting nuclear accumulation of IRF-3 and is associated with a reduced IRF-3 phosphorylation state. Thus, this investigation shows that the major structural protein of cytomegalovirus is committed to the modulation of the IRF-3 response, a primary mediator of the type I interferon response. By subverting IRF-3, the virus escapes throwing a central alarm devoted to both immediate antiviral control and regulation of the immune response.

scholarly journals Use of Transgenic HLA A*0201/Kb and HHD II Mice To Evaluate Frequency of Cytomegalovirus IE1-Derived Peptide Usage in Eliciting Human CD8 Cytokine Response

2003 ◽  
Vol 77 (7) ◽  
pp. 4457-4462 ◽  
Author(s):  
Ghislaine Gallez-Hawkins ◽  
Maria C. Villacres ◽  
Xiuli Li ◽  
Margaret C. Sanborn ◽  
Norma A. Lomeli ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
T Lymphocyte ◽  
Gamma Interferon ◽  
Cytokine Response ◽  
Interferon Response ◽  
Peptide Specificity ◽  
Cytolytic T Lymphocyte ◽  
Prominent Response

ABSTRACT Unlike the pp65 protein of human cytomegalovirus (CMV), which has an immunodominant peptide, pp65495-503, recognized by human CD8+ cells in the context of HLA A*0201, the fine peptide specificity for CMV IE1 has shown no such immunodominance. With the use of transgenic HLA A*0201/Kb and HHD II mice, a selected pool of IE1 peptides, including IE1p256-264, IE1p297-304, and IE1p316-324, were shown to stimulate cytolytic T-lymphocyte lysis in the context of HLA A*0201. Based on an intracellular gamma interferon response, IE1p297-304, a previously unrecognized CD8 epitope, triggered a prominent response to CMV IE1 in HLA A*0201 subjects.

scholarly journals Analysis of intracellular and intraviral localization of the human cytomegalovirus UL53 protein

2002 ◽  
Vol 83 (5) ◽  
pp. 1005-1012 ◽  
Author(s):  
P. Dal Monte ◽  
S. Pignatelli ◽  
N. Zini ◽  
N. M. Maraldi ◽  
E. Perret ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Nuclear Membrane ◽  
Human Fibroblasts ◽  
Nuclear Periphery ◽  
Structural Protein ◽  
Lamin B ◽  
Mature Virus Particle ◽  
Ul53 Gene ◽  
Simplex Virus

Human cytomegalovirus (HCMV) UL53 belongs to a family of conserved herpesvirus genes. In this work, the expression and localization of the UL53 gene product was analysed. Results obtained showed that pUL53 is a new structural protein. In infected human fibroblasts, pUL53 localizes in cytoplasmic perinuclear granular formations together with other structural viral proteins. In the nucleus, pUL53 forms patches at the nuclear periphery and co-localizes with lamin B at the internal nuclear membrane level. Immunoelectron microscopy studies have disclosed that nuclear pseudo-inclusions are labelled, whereas nucleocapsid formations within the intranuclear skein are negative. Furthermore, the mature virus particle maintains pUL53 at its tegumental level. These data suggest that pUL53 could be involved either in nucleocapsid maturation or in the egress of nucleocapsids from the nucleus to the cytoplasm through the nuclear membrane, a role compatible with the function hypothesized for UL31, its positional homologue in herpes simplex virus type 1.

scholarly journals Altered Cellular mRNA Levels in Human Cytomegalovirus-Infected Fibroblasts: Viral Block to the Accumulation of Antiviral mRNAs

2001 ◽  
Vol 75 (24) ◽  
pp. 12319-12330 ◽  
Author(s):  
Edward P. Browne ◽  
Bret Wing ◽  
David Coleman ◽  
Thomas Shenk
Keyword(s):  
Human Cytomegalovirus ◽  
Time Course ◽  
Interferon Response ◽  
Viral Gene ◽  
Mrna Levels ◽  
Cell Cycle Regulators ◽  
Mrna Accumulation ◽  
Human Diploid Fibroblasts ◽  
Chip Technology ◽  
Cellular Mrnas

ABSTRACT The effect of human cytomegalovirus (HCMV) infection on cellular mRNA accumulation was analyzed by gene chip technology. During a 48-h time course after infection of human diploid fibroblasts, 1,425 cellular mRNAs were found to be up-regulated or down-regulated by threefold or greater in at least two consecutive time points. Several classes of genes were prominently affected, including interferon response genes, cell cycle regulators, apoptosis regulators, inflammatory pathway genes, and immune regulators. The number of mRNAs that were up-regulated or down-regulated were roughly equal over the complete time course. However, for the first 8 h after infection, the number of up-regulated mRNAs was significantly less than the number of down-regulated mRNAs. By analyzing the mRNA expression profile of cells infected in the presence of cycloheximide, it was found that a minimum of 25 mRNAs were modulated by HCMV in the absence of protein synthesis. These included mRNAs encoded by a small number of interferon-responsive genes, as well as beta interferon itself. Cellular mRNA levels in cytomegalovirus-infected cells were compared to the levels in cells infected with UV-inactivated virus. The inactivated virus caused the up-regulation of a much greater number of mRNAs, many of which encoded proteins with antiviral roles, such as interferon-responsive genes and proinflammatory cytokines. These data argue that one or more newly synthesized viral gene products block the induction of antiviral pathways that are triggered by HCMV binding and entry.

The Linker of the Interferon Response Factor 3 Transcription Factor Is Not Unfolded

Biochemistry ◽  
2012 ◽  
Vol 51 (32) ◽  
pp. 6320-6327 ◽  
Author(s):  
Hem Shukla ◽  
Paulius Vaitiekunas ◽  
Ananya K. Majumdar ◽  
Anatoly I. Dragan ◽  
Emilios K. Dimitriadis ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Interferon Response ◽  
Response Factor

scholarly journals Interaction of Human Cytomegalovirus Tegument Proteins ppUL35 and ppUL35A with Sorting Nexin 5 Regulates Glycoprotein B (gpUL55) Localization

2018 ◽  
Vol 92 (9) ◽  
Author(s):  
Gregor Maschkowitz ◽  
Sabine Gärtner ◽  
Heike Hofmann-Winkler ◽  
Helmut Fickenscher ◽  
Michael Winkler
Keyword(s):  
Human Cytomegalovirus ◽  
Retrograde Transport ◽  
Viral Assembly ◽  
Glycoprotein B ◽  
Tegument Protein ◽  
Immunocompromised Patients ◽  
Structural Protein ◽  
Transport Pathway ◽  
Sorting Nexin ◽  
Sorting Nexin 5

ABSTRACTHuman cytomegalovirus (HCMV) is a widespread human pathogen that causes asymptomatic infection in healthy individuals but poses a serious threat to immunocompromised patients. During the late phase of HCMV infection, the viral capsid is transported to the cytoplasmic viral assembly center (cVAC), where it is enclosed by the tegument protein layer and the viral envelope. The cVAC consists of circularly arranged vesicles from thetrans-Golgi and endosomal networks. The HCMV gene UL35 encodes ppUL35 and its shorter form, ppUL35A. We have previously shown that the UL35 gene is involved in HCMV assembly, but it is unknown how UL35 proteins regulate viral assembly. Here we show that sorting nexin 5 (SNX5), a component of the retromer and part of the retrograde transport pathway, interacts with UL35 proteins. Expression of wild-type proteins but not mutants defective in SNX5 binding resulted in the cellular redistribution of the cation-independent mannose-6-phosphate receptor (CI-M6PR), indicating that UL35 proteins bind and negatively regulate SNX5 to modulate cellular transport pathways. Furthermore, binding of UL35 proteins to SNX5 was required for efficient viral replication and for transport of the most abundant HCMV glycoprotein B (gB; gpUL55) to the cVAC. These results indicate that ppUL35 and ppUL35A control the localization of the essential gB through the regulation of a retrograde transport pathway. Thus, this work is the first to define a molecular interaction between a tegument protein and a vesicular transport factor to regulate glycoprotein localization.IMPORTANCEHuman cytomegalovirus is ubiquitously present in the healthy population, but reactivation or reinfection can cause serious, life-threatening infections in immunocompromised patients. For completion of its lytic cycle, human cytomegalovirus induces formation of an assembly center where mature virus particles are formed from multiple viral proteins. Viral glycoproteins use separate vesicular pathways for transport to the assembly center, which are incompletely understood. Our research identified a viral structural protein which affects the localization of one of the major glycoproteins. We could link this change in glycoprotein localization to an interaction of the structural protein with a cellular protein involved in regulation of vesicle transport. This increases our understanding of how the virus intersects into cellular regulatory pathways to enhance its own replication.

Interferon response factor 3 is essential for house dust mite–induced airway allergy

2010 ◽  
Vol 126 (4) ◽  
pp. 836-844.e13 ◽  
Author(s):  
Thomas Marichal ◽  
Denis Bedoret ◽  
Claire Mesnil ◽  
Muriel Pichavant ◽  
Stanislas Goriely ◽  
...  
Keyword(s):  
House Dust ◽  
House Dust Mite ◽  
Interferon Response ◽  
Response Factor ◽  
Dust Mite

scholarly journals SARS-CoV-2 non-structural protein 1 inhibits the interferon response by causing depletion of key host signaling factors.

2021 ◽  
Author(s):  
Anil Kumar ◽  
Ray Ishida ◽  
Tania Strilets ◽  
Jamie Cole ◽  
Joaquin Lopez-Orozco ◽  
...  
Keyword(s):  
Causative Agent ◽  
Interferon Response ◽  
Type I ◽  
Structural Protein ◽  
Type I Ifns ◽  
Rapid Spread ◽  
Host Signaling ◽  
Infected Cells ◽  
Serious Disease ◽  
Taste And Smell

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic. While previous studies have shown that several SARS-CoV-2 proteins can antagonize the interferon (IFN) response, some of the mechanisms by which they do so are not well understood. In this study, we describe two novel mechanisms by which SARS-CoV-2 blocks the IFN pathway. Type I IFNs and IFN-stimulated genes (ISGs) were poorly induced during SARS-CoV-2 infection and once infection was established, cells were highly resistant to ectopic induction of IFNs and ISGs. Levels of two key IFN signaling pathway components, Tyk2 and STAT2 were significantly lower in SARS-CoV-2 infected cells. Expression of non-structural protein 1 (NSP1) or nucleocapsid in the absence of other viral proteins was sufficient to block IFN induction but only NSP1 was able to inhibit IFN signaling. Mapping studies suggest that NSP1 prevents IFN induction in part by blocking IRF3 phosphorylation. In addition, NSP1-induced depletion of Tyk2 and STAT2 dampened ISG induction. Together, our study provides new insights into how SARS-CoV-2 successfully evades the IFN system to establish infection. Importance SARS-CoV-2 is the causative agent of COVID-19, a serious disease that can have myriad of symptoms from loss of taste and smell to pneumonia and hypercoagulation. The rapid spread of SARS-CoV-2 can be attributed in part to asymptomatic transmission, where infected individuals shed large amounts of virus before the onset of disease. This is likely due to the ability of SARS-CoV-2 to effectively suppress the innate immune system, including the IFN response. Indeed, we show that the IFN response is efficiently blocked during SARS-CoV-2 infection, a process that is mediated in large part by non-structural protein 1 and nucleocapsid. Our study provides new insights on how SARS-CoV-2 evades the IFN response to successfully establish infection. These findings should be considered for the development and administration of therapeutics against SARS-CoV-2.

scholarly journals Expression and Characterization of a Novel Structural Protein of Human Cytomegalovirus, pUL25

1999 ◽  
Vol 73 (5) ◽  
pp. 3800-3809 ◽  
Author(s):  
Maria Concetta Battista ◽  
Giovanna Bergamini ◽  
Maria Cristina Boccuni ◽  
Fabio Campanini ◽  
Alessandro Ripalti ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Human Fibroblasts ◽  
Transcriptional Analysis ◽  
Structural Protein ◽  
Native Form ◽  
Flag Epitope ◽  
Reading Frame ◽  
Tegument Proteins ◽  
Infected Cells

ABSTRACT Human cytomegalovirus (HCMV) UL25 has recently been found to encode a new structural protein that is present in both virion and defective viral particles (C. J. Baldick and T. Shenk, J. Virol. 70:6097–6105, 1996). In the present work a polyclonal antibody was raised against a prokaryotic pUL25 fusion protein in order to investigate the biosynthesis and localization of the UL25 product (pUL25) during HCMV replication in human fibroblasts. Furthermore, pUL25 was transiently expressed in its native form and fused to the FLAG epitope, in COS7 and U373MG cells, in order to compare the properties of the isolated protein and that produced during infection. Immunoblotting analysis revealed a group of polypeptides, ranging from 80 to 100 kDa, in both transfected and infected cells; in vivo labeling experiments with infected cells demonstrated they are posttranslationally modified by phosphorylation. The transcriptional analysis of the UL25 open reading frame combined with the study of pUL25 biosynthesis showed true late kinetics for this protein in infected human fibroblasts. By indirect immunofluorescence both recombinant and viral pUL25 were detected exclusively in the cytoplasm of transfected or infected cells. Interestingly, pUL25 was shown to localize in typical condensed structures in the perinuclear region as already observed for other HCMV tegument proteins. Colocalization of ppUL99 in the same vacuoles suggests that these structure are endosomal cisternae, which are proposed to be a preferential site of viral particle envelopment. Our data suggest that pUL25 is most likely a novel tegument protein and possibly plays a key role in the process of envelopment.

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