scholarly journals Redistribution of Cellular and Herpes Simplex Virus Proteins from the Trans-Golgi Network to Cell Junctions without Enveloped Capsids

2004 ◽  
Vol 78 (21) ◽  
pp. 11519-11535 ◽  
Author(s):  
Todd W. Wisner ◽  
David C. Johnson
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Epithelial Cell ◽  
Cellular Protein ◽  
Cell Junctions ◽  
Specific Cell ◽  
Trans Golgi Network ◽  
Simplex Virus ◽  
Golgi Network ◽  
Virus Egress

ABSTRACT Herpes simplex virus (HSV) and other alphaherpesviruses assemble enveloped virions in the trans-Golgi network (TGN) or endosomes. Enveloped particles are formed when capsids bud into TGN/endosomes and virus particles are subsequently ferried to the plasma membrane in TGN-derived vesicles. Little is known about the last stages of virus egress from the TGN/endosomes to cell surfaces except that the HSV directs transport of nascent virions to specific cell surface domains, i.e., epithelial cell junctions. Previously, we showed that HSV glycoprotein gE/gI accumulates extensively in the TGN at early times after infection and also when expressed without other viral proteins. At late times of infection, gE/gI and a cellular membrane protein, TGN46, were redistributed from the TGN to epithelial cell junctions. We show here that gE/gI and a second glycoprotein, gB, TGN46, and another cellular protein, carboxypeptidase D, all moved to cell junctions after infection with an HSV mutant unable to produce cytoplasmic capsids. This redistribution did not involve L particles. In contrast to TGN membrane proteins, several cellular proteins that normally adhere to the cytoplasmic face of TGN, Golgi, and endosomal membranes remained primarily dispersed throughout the cytoplasm. Therefore, cellular and viral membrane TGN proteins move to cell junctions at late times of HSV infection when the production of enveloped particles is blocked. This is consistent with the hypothesis that there are late HSV proteins that reorganize or redistribute TGN/endosomal compartments to promote virus egress and cell-to-cell spread.

scholarly journals Herpes Simplex Virus gE/gI Must Accumulate in the trans-Golgi Network at Early Times and Then Redistribute to Cell Junctions To Promote Cell-Cell Spread

2006 ◽  
Vol 80 (7) ◽  
pp. 3167-3179 ◽  
Author(s):  
Aaron Farnsworth ◽  
David C. Johnson
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Junctions ◽  
Virus Spread ◽  
Neuronal Tissues ◽  
Mediate Cell ◽  
Simplex Virus ◽  
Golgi Network ◽  
Cell Spread ◽  
Cell Cell

ABSTRACT Herpes simplex virus (HSV) glycoprotein heterodimer gE/gI is necessary for virus spread in epithelial and neuronal tissues. Deletion of the relatively large gE cytoplasmic (CT) domain abrogates the ability of gE/gI to mediate HSV spread. The gE CT domain is required for the sorting of gE/gI to the trans-Golgi network (TGN) in early stages of virus infection, and there are several recognizable TGN sorting motifs grouped near the center of this domain. Late in HSV infection, gE/gI, other viral glycoproteins, and enveloped virions redistribute from the TGN to epithelial cell junctions, and the gE CT domain is also required for this process. Without the gE CT domain, newly enveloped virions are directed to apical surfaces instead of to cell junctions. We hypothesized that the gE CT domain promotes virus envelopment into TGN subdomains from which nascent enveloped virions are sorted to cell junctions, a process that enhances cell-to-cell spread. To characterize elements of the gE CT domain involved in intracellular trafficking and cell-to-cell spread, we constructed a panel of truncation mutants. Specifically, these mutants were used to address whether sorting to the TGN and redistribution to cell junctions are necessary, and sufficient, for gE/gI to promote cell-to-cell spread. gE-519, lacking 32 C-terminal residues, localized normally to the TGN early in infection and then trafficked to cell junctions at late times and mediated virus spread. By contrast, mutants gE-495 (lacking 56 C-terminal residues) and gE-470 (lacking 81 residues) accumulated in the TGN but did not traffic to cell junctions and did not mediate cell-to-cell spread. A fourth mutant, gE-448 (lacking most of the CT domain), did not localize to cell junctions and did not mediate virus spread. Therefore, the capacity of gE/gI to promote cell-cell spread requires early localization to the TGN, but this is not sufficient for virus spread. Additionally, gE CT sequences between residues 495 and 519, which contain no obvious cell sorting motifs, are required to promote gE/gI traffic to cell junctions and cell-to-cell spread.

scholarly journals Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

2015 ◽  
Vol 89 (19) ◽  
pp. 9841-9852 ◽  
Author(s):  
Kathryne E. Taylor ◽  
Karen L. Mossman
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Replication ◽  
Cellular Protein ◽  
Viral Gene ◽  
Late Gene Expression ◽  
Simplex Virus ◽  
Golgi Network ◽  
Hsv 1

ABSTRACTIt has recently been proposed that the herpes simplex virus (HSV) protein ICP0 has cytoplasmic roles in blocking antiviral signaling and in promoting viral replication in addition to its well-known proteasome-dependent functions in the nucleus. However, the mechanisms through which it produces these effects remain unclear. While investigating this further, we identified a novel cytoplasmic interaction between ICP0 and the poorly characterized cellular protein WDR11. During an HSV infection, WDR11 undergoes a dramatic change in localization at late times in the viral replication cycle, moving from defined perinuclear structures to a dispersed cytoplasmic distribution. While this relocation was not observed during infection with viruses other than HSV-1 and correlated with efficient HSV-1 replication, the redistribution was found to occur independently of ICP0 expression, instead requiring viral late gene expression. We demonstrate for the first time that WDR11 is localized to thetrans-Golgi network (TGN), where it interacts specifically with some, but not all, HSV virion components, in addition to ICP0. Knockdown of WDR11 in cultured human cells resulted in a modest but consistent decrease in yields of both wild-type and ICP0-null viruses, in the supernatant and cell-associated fractions, without affecting viral gene expression. Although further study is required, we propose that WDR11 participates in viral assembly and/or secondary envelopment.IMPORTANCEWhile the TGN has been proposed to be the major site of HSV-1 secondary envelopment, this process is incompletely understood, and in particular, the role of cellular TGN components in this pathway is unknown. Additionally, little is known about the cellular functions of WDR11, although the disruption of this protein has been implicated in multiple human diseases. Therefore, our finding that WDR11 is a TGN-resident protein that interacts with specific viral proteins to enhance viral yields improves both our understanding of basic cellular biology as well as how this protein is co-opted by HSV.

scholarly journals Cellular Protein Kinase D Modulators Play a Role during Multiple Steps of Herpes Simplex Virus 1 Egress

2018 ◽  
Vol 92 (23) ◽  
Author(s):  
Élisabeth Roussel ◽  
Roger Lippé
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Protein Kinase ◽  
Cellular Protein ◽  
Host Protein ◽  
Protein Kinase D ◽  
Herpes Simplex Virus 1 ◽  
Nuclear Egress ◽  
Simplex Virus ◽  
Golgi Network

ABSTRACTThe assembly of new herpes simplex virus 1 (HSV-1) particles takes place in the nucleus. These particles then travel across the two nuclear membranes and acquire a final envelope from a cellular compartment. The contribution of the cell to the release of the virus is, however, little known. We previously demonstrated, using a synchronized infection, that the host protein kinase D and diacylglycerol, a lipid that recruits the kinase to thetrans-Golgi network (TGN), promote the release of the virus from that compartment. Given the role this cellular protein plays in the herpes simplex virus 1 life cycle and the many molecules that modulate its activity, we aimed to determine to what extent this virus utilizes the protein kinase D pathway during a nonsynchronized infection. Several molecular protein kinase D (PKD) regulators were targeted by RNA interference and viral production monitored. Surprisingly, many of these modulators negatively impacted the extracellular release of the virus. Overexpression studies, the use of pharmacological reagents, and assays to monitor intracellular lipids implicated in the biology of PKD suggested that these effects were oddly independent of total intracellular diacylglycerol levels. Instead, mapping of the viral intermediates by electron microscopy suggested that some of these modulators could regulate distinct steps along the viral egress pathway, notably nuclear egress. Altogether, this suggests a more complex contribution of PKD to HSV-1 egress than originally anticipated and new research avenues to explore.IMPORTANCEViruses are obligatory parasites that highjack numerous cellular functions. This is certainly true when it comes to transporting viral particles within the cell. Herpesviruses share the unique property of traveling through the two nuclear membranes by subsequent budding and fusion and acquiring their final envelope from a cellular organelle. Albeit disputed, the overall evidence from many laboratories points to thetrans-Golgi network (TGN) as the source of that membrane. Moreover, past findings revealed that the host protein kinase D (PKD) plays an important role at that stage, which is significant given the known implication of that protein in vesicular transport. The present findings suggest that the PKD machinery not only affects the late stages of herpes simplex virus I egress but also modulates earlier steps, such as nuclear egress. This opens up new means to control these viruses.

scholarly journals Cytoplasmic Domain of Herpes Simplex Virus gE Causes Accumulation in the trans-Golgi Network, a Site of Virus Envelopment and Sorting of Virions to Cell Junctions

2001 ◽  
Vol 75 (4) ◽  
pp. 1928-1940 ◽  
Author(s):  
Tom N. McMillan ◽  
David C. Johnson
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Epithelial Cells ◽  
Chimeric Protein ◽  
Cell Junctions ◽  
Cytoplasmic Vesicles ◽  
Simplex Virus ◽  
Golgi Network ◽  
Late Stages ◽  
Cell Spread

ABSTRACT Alphaherpesviruses express a heterodimeric glycoprotein, gE/gI, that facilitates cell-to-cell spread between epithelial cells and neurons. Herpes simplex virus (HSV) gE/gI accumulates at junctions formed between polarized epithelial cells at late times of infection. However, at earlier times after HSV infection, or when gE/gI is expressed using virus vectors, the glycoprotein localizes to thetrans-Golgi network (TGN). The cytoplasmic (CT) domains of gE and gI contain numerous TGN and endosomal sorting motifs and are essential for epithelial cell-to-cell spread. Here, we swapped the CT domains of HSV gE and gI onto another HSV glycoprotein, gD. When the gD-gICT chimeric protein was expressed using a replication-defective adenovirus (Ad) vector, the protein was found on both the apical and basolateral surfaces of epithelial cells, as was gD. By contrast, the gD-gECT chimeric protein, gE/gI, and gE, when expressed by using Ad vectors, localized exclusively to the TGN. However, gD-gECT, gE/gI, and TGN46, a cellular TGN protein, became redistributed largely to lateral surfaces and cell junctions during intermediate to late stages of HSV infection. Strikingly, gE and TGN46 remained sequestered in the TGN when cells were infected with a gI−HSV mutant. The redistribution of gE/gI to lateral cell surfaces did not involve widespread HSV inhibition of endocytosis because the transferrin receptor and gE were both internalized from the cell surface. Thus, gE/gI accumulates in the TGN in early phases of HSV infection then moves to lateral surfaces, to cell junctions, at late stages of infection, coincident with the redistribution of a TGN marker. These results are related to recent observations that gE/gI participates in the envelopment of nucleocapsids into cytoplasmic vesicles (A. R. Brack, B. G. Klupp, H. Granzow, R. Tirabassi, L. W. Enquist, and T. C. Mettenleiter, J. Virol. 74:4004–4016, 2000) and that gE/gI can sort nascent virions from cytoplasmic vesicles specifically to the lateral surfaces of epithelial cells (D. C. Johnson, M. Webb, T. W. Wisner, and C. Brunetti, J. Virol. 75:821–833, 2000). Therefore, gE/gI localizes to the TGN, through interactions between the CT domain of gE and cellular sorting machinery, and then participates in envelopment of cytosolic nucleocapsids there. Nascent virions are then sorted from the TGN to cell junctions.

scholarly journals Elucidation of the Block to Herpes Simplex Virus Egress in the Absence of Tegument Protein UL16 Reveals a Novel Interaction with VP22

2013 ◽  
Vol 88 (1) ◽  
pp. 110-119 ◽  
Author(s):  
J. L. Starkey ◽  
J. Han ◽  
P. Chadha ◽  
J. A. Marsh ◽  
J. W. Wills
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Tegument Protein ◽  
Simplex Virus ◽  
Virus Egress

scholarly journals Herpes Simplex Virus Entry by a Nonconventional Endocytic Pathway

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Giulia Tebaldi ◽  
Suzanne M. Pritchard ◽  
Anthony V. Nicola
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Epithelial Cells ◽  
Retrograde Transport ◽  
Endocytic Pathway ◽  
Host Cells ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Golgi Network ◽  
Hsv 1

ABSTRACT Herpes simplex virus 1 (HSV-1) causes significant morbidity and mortality in humans worldwide. HSV-1 enters epithelial cells via an endocytosis mechanism that is low-pH dependent. However, the precise intracellular pathway has not been identified, including the compartment where fusion occurs. In this study, we utilized a combination of molecular and pharmacological approaches to better characterize HSV entry by endocytosis. HSV-1 entry was unaltered in both cells treated with small interfering RNA (siRNA) to Rab5 or Rab7 and cells expressing dominant negative forms of these GTPases, suggesting entry is independent of the conventional endo-lysosomal network. The fungal metabolite brefeldin A (BFA) and the quinoline compound Golgicide A (GCA) inhibited HSV-1 entry via beta-galactosidase reporter assay and impaired incoming virus transport to the nuclear periphery, suggesting a role for trans-Golgi network (TGN) functions and retrograde transport in HSV entry. Silencing of Rab9 or Rab11 GTPases, which are involved in the retrograde transport pathway, resulted in only a slight reduction in HSV infection. Together, these results suggest that HSV enters host cells by an intracellular route independent of the lysosome-terminal endocytic pathway. IMPORTANCE Herpes simplex virus 1 (HSV-1), the prototype alphaherpesvirus, is ubiquitous in the human population and causes lifelong infection that can be fatal in neonatal and immunocompromised individuals. HSV enters many cell types by endocytosis, including epithelial cells, the site of primary infection in the host. The intracellular itinerary for HSV entry remains unclear. We probed the potential involvement of several Rab GTPases in HSV-1 entry and suggest that endocytic entry of HSV-1 is independent of the canonical lysosome-terminal pathway. A nontraditional endocytic route may be employed, such as one that intersects with the trans-Golgi network (TGN). These results may lead to novel targets for intervention.

scholarly journals Stable induction of a 51K cellular protein in neuronal cells surviving herpes simplex virus type 1 infection

Virology ◽  
1985 ◽  
Vol 142 (2) ◽  
pp. 398-405
Author(s):  
Alan L. Goldin ◽  
Rozanne M. Sandri-Goldin ◽  
Joseph C. Glorioso ◽  
Myron Levine
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Neuronal Cells ◽  
Cellular Protein ◽  
Simplex Virus
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