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Journal of Virology, August 2006, p. 7756-7759, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00587-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus 1 Precludes Replenishment of the Short-Lived Receptor of Tumor Necrosis Factor Alpha by Virion Host Shutoff-Dependent Degradation of Its mRNA

Li Liang and Bernard Roizman*

Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, 910 East 58th Street, Chicago, Illinois 60637

Received 23 March 2006/ Accepted 16 May 2006


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ABSTRACT
 
Cell function is tightly regulated by surface receptors. Earlier reports showed that herpes simplex virus 1 regulates by diverse mechanisms the presentation of antigenic peptides, downregulates the signaling pathways associated with receptor tyrosine kinases, and posttranslationally modifies members of the Src family of protein kinases. Here we report that the receptor for tumor necrosis factor alpha (TNF-R1) rapidly disappears from both the cell surface and total cell lysates in cells infected with wild-type virus or a variety of mutants but not in cells infected with the mutant {Delta}UL41, which lacks the UL41 gene, the virion host shutoff gene. The half-life of TNF-R1 appears to be less than 30 min in both mock-infected and infected cells. The disappearance of TNF-R1 correlates with the disappearance of cytoplasmic TNF-R1 mRNA in wild-type-virus-infected cells. The results suggest that by degrading the TNFR1 mRNA, the virus precludes the replenishment of naturally decaying TNF-R1.


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TEXT
 
The cell surface is a giant antenna that receives signals from and transmits signals to the environment. When cells become infected with a virus, some of the signals emanating from the cells inform the environment of the presence of an intruder. Receptors, responding to the emanating signals, attempt to curtail viral replication or induce the infected cells to commit suicide. It is not surprising that viruses have evolved mechanisms to curtail the outflow of signals, to degrade receptors of signals that could have a deleterious effect on viral replication, or at the very least to block the execution of the signals received by the receptors. In the case of herpes simplex virus 1 (HSV-1), clear examples of interference with signaling are evidence that the virus blocks the presentation of antigenic peptides on the cell surface by major histocompatibility complex class I and II proteins (12, 16, 24, 27, 30). More recent studies indicate that interference with signaling is more pervasive. HSV-1 blocks exogenous interferon from affecting viral replication through degradation of the promyelocytic leukemia protein, the organizer of ND10 nuclear structure, which appears to regulate interferon response genes (3, 5), the acceleration of turnover of JAK1 (33), and degradation of IRF3 (22). At least one HSV-1 product, infected-cell protein 0 (ICP0), has been shown to down regulate the receptor tyrosine kinases using epidermal growth factors as prototypic receptors (19). Given this background, it was of interest to determine the fate of the receptors of tumor necrosis factor alpha (TNF-{alpha}).

TNF-{alpha} is secreted by a variety of cells, including natural killer cells, T lymphocytes, macrophages, etc. In turn, TNF-{alpha} induces a wide variety of genes that play significant roles in immune and inflammatory responses. The protein has two major receptors, TNF-R1 and TNF-R2. TNF-R1 is expressed in most tissues, whereas TNF-R2 is typically found in cells of the immune system. The receptors share sequences in their ectodomains but differ with respect to cytoplasmic domains. Activation of both receptors, however, may lead to activation of antiviral responses and cell death. TNF-{alpha} has been shown to inhibit HSV as well as other viruses. Extensive literature has documented both the antiviral effects of TNF-{alpha} and the properties of the receptors (32). A central goal of the studies described in this report was to determine the fate of the TNF-R1 receptors present on the surface of several cell lines. In this report, we show that TNF-{alpha} receptor disappears very rapidly from infected cells and that the disappearance is related to the function of the virion host shutoff factor encoded by the UL41 open reading frame.

In the first series of experiments, we quantified the TNF-R1 in total cell lysates and on the surfaces of infected cells. Replicate HEp-2 cells were mock infected or exposed to 10 PFU of HSV-1(F) per cell and incubated for 6 h at 37°C. To prepare total cell lysates, the cells were harvested by scraping into lysis buffer (1% NP-40, 0.5% sodium deoxycholate, 150 mM NaCl) followed by brief sonication. The proteins were denatured by boiling in sodium dodecyl sulfate (SDS) sample buffer for 5 min and subjected to electrophoresis on a denaturing polyacrylamide gel. For surface protein extraction, the cells were rinsed twice with ice-cold phosphate-buffered saline (PBS) and reacted with 1 mg of sulfo-NHS-LC-biotin reagent (no. 21335; Pierce) per ml at 4°C for 30 min and then rinsed three times with 100 mM glycine in PBS to quench and remove the biotin reagent. The cells were then harvested and lysed by scraping into binding buffer (0.1% SDS, 1% NP-40, 0.5% sodium deoxycholate, fresh protease inhibitor) at 4°C, followed by brief sonication. Immobilized streptavidin agarose beads (no. 53117; Pierce) were rinsed in binding buffer twice and reacted with the lysate overnight at 4°C. The streptavidin-bound complex was collected and rinsed five times with binding buffer. The biotinylated proteins were eluted from the beads with 8 M guanidine HCl. Both total and extracted cell surface proteins were electrophoretically separated on a 10% denaturing polyacrylamide gel, transferred to a nitrocellulose sheet, and reacted with anti-TNF-R1 antibody. As shown in Fig. 1A, both total and cell surface amounts decreased drastically after infection. The decrease in the amount of TNF-R1 on the surface of infected cells mirrored the decrease in the total amount of TNF-R1 accumulating in mock-infected and infected cells.


Figure 1
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  		FIG. 1. TNF-R1 downregulation in infected HEp-2 cells. (A) HEp-2 cells were mock infected or exposed to 10 PFU of HSV-1(F) per cell. The cells were harvested 6 h after infection and total cell lysate or extracted surface proteins were separated on 10% denaturing polyacrylamide gel, transferred to a nitrocellulose gel and reacted with anti-TNF-R1. (B) Time course of down regulation of total TNF-R1 in infected cells. HEp-2 cells were mock infected or exposed to 5 PFU of HSV-1(F), {Delta}ICP0, ICP0 RING finger mutant {Delta}R-F, or {Delta}UL41 per cell. Cells were harvested at 2, 4, and 8 h after infection. Total cell lysates were separated on 10% denaturing polyacrylamide gels and immunoblotted with anti-TNF-R1. A, cross-reacting cellular protein that served as a loading control.

The objective of the second series of experiments was to measure the time course of disappearance of TNF-R1 from wild-type-virus-infected HEp-2 cells. Replicate cultures of HEp-2 cells were mock infected or exposed to 5 PFU of HSV-1(F), {Delta}ICP0, C116G/C156A ({Delta}R-F), or {Delta}UL41 per cell. HSV-1(F) is the prototype wild-type strain used in this laboratory (8). {Delta}ICP0 lacks the gene encoding ICP0, and {Delta}R-F carries amino acid substitutions (C116G/C156A) that disable the RING finger domain of ICP0 (18, 20). {Delta}UL41 contains the coding sequences of ß-galactosidase inserted into the UL41 open reading frame (26). The cultures were harvested at 2, 4, or 8 h after infection, and total cell lysates were processed as above and reacted with TNF-R1 mouse monoclonal antibody. As shown in Fig. 1B, TNF-R1 protein significantly decreased or virtually disappeared from cells at 2 h after infection with all viruses but {Delta}UL41. In {Delta}UL41-infected cells, the amount of TNF-R1 protein decreased, but not nearly as rapidly as in cells infected with wild-type virus. Thus, at 8 h after infection the amount of TNF-R1 protein in lysates of {Delta}UL41-infected cells was higher than that in wild-type-virus-infected cells harvested at 2 h after infection.

The objective of the third series of experiments was to determine whether the rapid disappearance of TNF-R1 was UL41 dependent in other cell lines. In this series of experiments, replicate cultures of HEp-2 cells, U2OS, or HeLa cells were mock infected or exposed to 10 PFU of HSV-1(F), {Delta}ICP0, {Delta}R-F, {Delta}UL41 or d120 per cell. Mutant virus d120 lacks the gene encoding ICP4 (7). The cells were harvested at 6 h after infection, processed as above, and reacted with anti-TNF-R1 antibody. In each cell line tested, TNF-R1 decayed in cells exposed to wild-type or mutant viruses except those exposed to {Delta}UL41 (Fig. 2). In cells infected with this mutant virus, the amount of TNF-R1 decreased but were significantly higher than in other infected cell cultures. We conclude that the decay in TNF-R1 was UL41 virus dependent but not cell type dependent.


Figure 2
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  		FIG. 2. Downregulation of TNR-R1 is cell type independent. Replicate cultures of HEp-2, U2OS, or HeLa cells were mock infected or exposed to 10 PFU of the indicated virus per cell. The cells were harvested at 6 h after infection, and total cell lysates were separated on 10% denaturing polyacrylamide gels and immunoblotted with anti-TNF-R1 antibody.

The objective of the fourth series of experiments was to determine whether the life spans of TNF-R1 in mock-infected and infected cells were similar. In essence, the question posed was whether TNF-R1 was actively degraded in infected cells in contradistinction to its fate in uninfected cells. Replicate cultures of HEp-2 cells were mock infected or exposed to 10 PFU of HSV-1(F) or {Delta}UL41 per cell. Cycloheximide (100 µg/ml) was added at the time of mock infection or exposure to virus and maintained until harvest at 0.5, 1.0, 1.4, 2.0 or 2.5 h after infection. The total cell lysates were processed as described above and reacted with monoclonal antibody to TNF-R1 or polyclonal antibody to actin. The salient feature of the results shown in Fig. 3 is that at 0.5 h after exposure to cycloheximide in either infected or mock-infected cells, the amount of TNF-R1 was less than half the amount present at the time of addition of the drug (0 h). The results indicate that the half-life of TNF-R1 is less than 0.5 h in both infected and mock-infected cells. The experiment did not elicit evidence that TNF-R1 protein was actively degraded in infected cells.


Figure 3
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  		FIG. 3. Half-life of TNF-R1 in infected HEp-2 cells. HEp-2 cells were mock infected or exposed to 10 PFU of HSV-1(F) or {Delta}UL41 per cell. Cycloheximide (100 µg/ml) was added at the time of exposure of cells to virus (0 h) and maintained during the infection. The cells were harvested at 0, 0.5, 1.0, 1.5, 2.0, or 2.5 h after infection. Total cell lysates were separated on a 10% denaturing polyacrylamide gel and immunoblotted with anti-TNF-R1 antibody or antiactin antibody.

The fundamental property of the virion host shutoff protein encoded by UL41 is that it acts as an endoribonuclease that selectively degrades mRNA (9, 29). If the disappearance of TNF-R1 protein was related to the nucleolytic activity of the UL41 protein, it would be expected that the TNF-R1 mRNA would be degraded in wild-type-virus-infected cells but not in mutant-virus-infected cells. In this series of experiments, replicate cultures of HeLa cells were mock infected or exposed to 5 PFU of HSV-1(F) or {Delta}UL41 virus per cell. At 0, 1, 3, or 7 h after infection, cytoplasmic RNA was isolated, separated on a 1% agarose gel, and probed with 32P-labeled full-length TNF-R1 cDNA as described elsewhere (9). TNF-R1 fragment was amplified by RT-PCR of cytoplasmic RNA using primers TNFRSF1A forward0 (5'-CATGGGCCTCTCCACCGTGCCTG-3') and TNFRSF1AB (5'-AGCCTCATCTGAGAAGACTGG-3'). Figure 4 shows a photograph of an ethidium bromide-stained gel of electrophoretically separated RNA: the rRNA serves as a loading control. The autoradiogram shown in Fig. 4 indicates that the mRNA encoding TNF-R rapidly decreased from wild-type-virus-infected cells but remained at a relatively stable level in cells infected with {Delta}UL41. These results are consistent with and support the hypothesis that UL41 protein acts by degrading the mRNA of TNF-R1.


Figure 4
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  		FIG. 4. Northern blot of TNF-R1 in infected HeLa cells. HeLa cells were mock infected or exposed to 5 PFU of virus per cell. Cells were harvested at 1, 3, or 7 h after infection, and cytoplasmic RNAs were extracted and separated on a 1% agarose gel followed by Northern blot analysis with 32P-labeled full-length TNF-R1 cDNA.

The fundamental conclusion of the studies presented in this report is that two factors account for the disappearance of TNF-R1. First, the receptor has a very short half-life in all of the cell lines tested. Therefore, steady-state levels of TNF-R1 require continuous replenishment by translation of its mRNA. In these studies we have shown that the mRNA levels decrease in a UL41-dependent manner. Hence, the disappearance of TNF-R1 is the result of failure to replenish of the protein because of the degradation of its mRNA. It is of interest that {Delta}UL41 mutants are avirulent in experimental animal systems. Although the UL41 protein affects many different host mRNAs, there arises the question of whether the inability to block the interaction of TNF-{alpha} with its receptor contributes to the virulence of this mutant.

HSV employs a large number of diverse strategies to inactivate host functions inimical to its replication and spread. Some proteins are degraded by the action of E3 ligase activity of ICP0 (4, 6, 11, 14, 19, 21, 25, 31). Others are inactivated by phosphorylation by the viral protein kinases (2, 23, 28), by translocation into inoperative compartments of the cell (10, 13, 17, 34), or by recruitment to perform functions different from those expressed in uninfected cells (1, 15). In the case of TNF-R1, the strategy of HSV-1 is to take advantage of the short natural longevity of the protein.


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ACKNOWLEDGMENTS
 
We thank B. Taddeo, A. P. W. Poon, G. Zhou, and H. Gu for advice and useful discussions.

These studies were aided by National Cancer Institute grants CA87661, CA83939, CA71933, CA78766, and CA88860.


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FOOTNOTES
 
* Corresponding author. Mailing address: Marjorie B. Kovler Viral Oncology Laboratories, The University of Chicago, 910 East 58th St., Chicago, IL 60637. Phone: (773) 702-1898. Fax: (773) 702-1631. E-mail: bernard.roizman{at}bsd.uchicago.edu. Back


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Journal of Virology, August 2006, p. 7756-7759, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.00587-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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