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Journal of Virology, May 1999, p. 4456-4460, Vol. 73, No. 5
Department of Tumor Virology,
Received 16 November 1998/Accepted 1 February 1999
Earlier reports (Y. Kawaguchi, R. Bruni, and B. Roizman, J. Virol. 71:1019-1024, 1997; Y. Kawaguchi, C. Van Sant, and B. Roizman, J. Virol. 72:1731-1736, 1998) showed that herpes simplex
virus 1 (HSV-1) infection causes the hyperphosphorylation of
translation elongation factor 1 The herpesviruses have been
subdivided into three subfamilies based on molecular and biological
properties (27). Although members of the three herpesvirus
subfamilies exhibit a wide range of biological properties and the range
of pathogenic manifestations (27), their genomes contain a
significant number of conserved genes. These conserved genes
include genes encoding glycoproteins (e.g., gB and gH),
regulatory proteins (e.g., ICP27), and a large array of conserved
enzymes involved in posttranslational modification of protein (e.g.,
protein kinases), DNA synthesis (e.g., DNA polymerase, helicase, and
primase), and processing of proteins (e.g., protein kinase)
(28). This conservation suggests that these gene products play an essential role in the life cycle of herpesviruses.
In an earlier study, we showed that infection of cells with herpes
simplex virus 1 (HSV-1), a prototype of alphaherpesvirus, causes
extensive hyperphosphorylation of translation elongation factor 1 (i) EF-1 (ii) EF-1 (iii) The UL13 gene was originally reported to contain
motifs conserved in eukaryotic protein kinase (1, 30) and in
subsequent studies was associated with the phosphorylation of itself,
EF-1 (iv) The HCMV protein UL97 has homology to UL13
of HSV, so the protein was predicted to be a protein kinase
(1). Interestingly, the UL97 protein
phosphorylates ganciclovir, a nucleotide analog effective against
HCMV infection, and therefore, the viral protein can act as a
deoxynucleoside kinase (14, 31). Studies on
recombinant HSV-1 in which the UL13 protein was
replaced by its HCMV homologue showed that UL97 can
substitute for the UL13 protein kinase (Fig. 1), and only recently it has been shown
to be a serine/threonine kinase that phosphorylates itself (8,
21). The results supported the hypothesis that
UL97 is a protein kinase with the unusual property of
being able to phosphorylate deoxynucleosides.
In this report we demonstrate that EF-1 Vero and human lung fibroblast (HLF) cells were obtained from the
American Type Culture Collection and Aviron (Mountain View, Calif.), respectively. Madin-Darby bovine kidney (MDBK) and
cloned porcine kidney (CPK) cells were provided by H. Ohtsuka
(The University of Tokyo). Crandell feline kidney (CRFK) cells were a
gift from T. Mikami (The University of Tokyo). Fetal horse
kidney (FHK) cells were isolated as described elsewhere (15)
and used within seven passages of primary culture. The cell lines were
grown in Dulbecco's modified Eagle's medium supplemented with either
10% fetal calf serum (HLF, MDBK, CPK, or CRFK cells) or 5% fetal calf serum (Vero cells).
The properties of the virus strains HSV-1(F), HSV-2(G), HCMV(Towne) and
the genetically engineered recombinant viruses listed in Table
1 have been described elsewhere (5,
9, 21, 22, 24, 25). Feline herpesvirus 1 [FHV-1(C7301)] (17) was provided by T. Mikami. Bovine
herpesvirus 1 [BHV-1(LA)] and pseudorabies virus
[PRV(Indiana)] were supplied by H. Ohtsuka. Japanese field isolates of equine herpesvirus 2 [EHV-2(87C26) and EHV-2(87C33)] were
isolated with FHK cells as described elsewhere (15). gB regions of the genomes of the EHV-2 strains were amplified, cloned into
pGEM-T vector (Promega), and sequenced. The sequences were completely identical to the published sequence of the EHV-2 gB (32).
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Cellular Elongation Factor 1
Is Modified in
Cells Infected with Representative Alpha-, Beta-, or
Gammaherpesviruses
ABSTRACT
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Abstract
Text
References
(EF-1) and that the modification
of EF-1 is the consequence of direct phosphorylation by a viral
protein kinase encoded by the UL13 gene of HSV-1. The
UL13 gene is conserved in members of all herpesvirus
subfamilies. Here we report the following. (i) In various mammalian
cells, accumulation of the hyperphosphorylated form of EF-1 is
observed after infection with alpha-, beta-, and
gammaherpesviruses, including HSV-2, feline herpesvirus 1, pseudorabiesvirus, bovine herpesvirus 1, human cytomegalovirus (HCMV),
and equine herpesvirus 2. (ii) In human lung fibroblast cells infected
with recombinant HSV-1 lacking the UL13 gene, the
hypophosphorylated form of EF-1 is a minor species, whereas the
amount of the hyperphosphorylated form of EF-1 significantly
increases in cells infected with the recombinant HSV-1 in which
UL13 had been replaced by HCMV UL97, a
homologue of UL13. These results indicate that the
posttranslational modification of EF-1 is conserved herpesvirus
function and the UL13 homologues may be responsible for the
universal modification of the translation factor.
TEXT
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Abstract
Text
References
(EF-1) (11). In a subsequent study, we found that the
gene product of HSV-1 responsible for EF-1 hyperphosphorylation is a
viral protein kinase encoded by the UL13 gene
(13). This observation and the fact that the amino acid
sequence that encodes UL13 protein kinase is conserved in
members of all subfamilies of the family Herpesviridae led
us to investigate whether EF-1 is also posttranslationally modified
in cells infected with representative members of all subfamilies of
herpesviruses. In this report, we present evidence that this is in fact
the case. In one instance, we have specifically related the
modification of EF-1 to the protein kinase encoded by
UL97, the human cytomegalovirus (HCMV) homologue of the
UL13 gene of HSV-1. Relevant to this report are the
following observations.
is a subunit of EF-1, a complex of proteins which
mediate the elongation of polypeptide chains during
translation of mRNA (16, 18, 26, 33). EF-1
transports aminoacyl tRNA for binding to ribosomes concurrent with the
hydrolysis of GTP. EF-1 is a component of the
EF-1
-EF-1
-EF-1 complex which is responsible for GDP-GTP
exchange on EF-1, and numerous studies have ascribed to
EF-1 regulatory functions (16, 19, 26).
interacts with two viral proteins in cells infected with
HSV-1. As reported elsewhere, EF-1 interacts with ICP0, an protein known primarily for its function as a promiscuous transactivator. Thus, ICP0 interacts physically in the yeast two-hybrid system with EF-1, and the domain of ICP0 interacting with
EF-1 affects translational efficiency in vitro (11). ICP0
is a multifunctional protein which interacts with and modulates many
key cellular functions, including transcription (7, 10),
translation (11), cell cycle regulation (12), and
the protein degradation pathway (6). EF-1 also interacts
with and is hyperphosphorylated by the protein kinase encoded by the
UL13 gene. The observation that two viral proteins interact
with EF-1 suggests that this protein plays an important role in the
viral life cycle.
, and several viral proteins (e.g., ICP22, ICP0, and gE)
(2, 13, 20, 22, 25). Recent evidence based on experiments on
purified UL13 protein unambiguously demonstrated that it is a protein kinase (3). The UL13 protein is
packaged into virion, and indeed, a protein kinase activity is
associated with purified virions (2, 23). Experiments with
genetically engineered viruses lacking the UL13 gene showed
that the viral protein kinase affects the accumulation of ICP0 and a
subset of proteins, suggesting that the kinase activity of
UL13 may play a regulatory function (24).
View larger version (14K):
[in a new window]
FIG. 1.
Schematic diagram of the sequence arrangement of the
HSV-1 genome showing the location of the UL13 gene. Line 1 shows a linear representation of the HSV-1(F) genome. The unique
sequences are represented as the unique long (UL) and
unique short (US) regions. The terminal repeats flanking
the unique sequences are shown as open rectangles and their
designations are given above. Line 2 shows an expanded section of the
genome domain containing UL12, UL13, and
UL14 open reading frames. The coding regions are
represented by arrows. Line 3 shows R7356 with a deletion spanning
HindIII (H) to BstEII (B) restriction
endonuclease sites within the UL13 coding domain. Line 4 shows R4969, a recombinant virus in which the UL13 domain
spanning HindIII to BstEII restriction
endonuclease sites was replaced with the coding sequence of HCMV
UL97 fused to the promoter of the UL26.5 gene
(pUL26.5).
is commonly modified in
cells infected with representative members of the alpha-, beta-, and
gammaherpesvirus subfamilies and that this phenomenon is not unique to
HSV-1-infected cells. We also present evidence that HCMV
UL97 can mediate the modification of EF-1.
TABLE 1.
Genotype and phenotype of recombinant viruses used in
this study
The rabbit polyclonal antibody to EF-1 was generated as
described elsewhere (11). The electrophoretically
separated proteins transferred to nitrocellulose sheets were
reacted with the antibody to EF-1 as described previously (11,
12).
The objective of the first series of experiments was to determine
whether alphaherpesviruses other than HSV-1 also cause
hyperphosphorylation of EF-1 in infected cells. As reported
previously, EF-1 consists of two predominant forms, a
hypophosphorylated form (apparent Mr of 38,000)
and a hyperphosphorylated form (apparent Mr of
40,000) (11, 13, 19, 29). The polyclonal antibody used in
this study can readily detect both forms of EF-1, and the pattern of
bands of EF-1 radiolabeled by 32Pi is exactly the same
as that of EF-1 detected by Western blotting (11, 13). To
monitor changes in EF-1, Vero, CRFK, CPK and MDBK cells were
harvested 24 h after mock infection or infection with HSV-2(G),
FHV-1(C7301), PRV(Indiana), and BHV-1(LA), respectively, solubilized, electrophoretically separated in denaturing gels, electrophoretically transferred to nitrocellulose sheets, and reacted
with the rabbit polyclonal antibody to EF-1. The results were as follows.
(i) In mock-infected Vero and CRFK cells, the two predominant bands
migrating with Mrs of 38,000 and 40,000, respectively, were detected (Fig. 2) as
described previously (11, 13). The result that the
polyclonal antibody raised against human EF-1-glutathione S-transferase fusion protein detected EF-1 in feline
cells (Fig. 2) indicates that the epitopes to which the antibody is
directed are conserved in nonhuman EF-1. In cells infected with
HSV-2(G) or FHV-1(C7301), the amount of EF-1 protein in
slower-migrating bands was significantly increased (Fig. 2).
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(ii) In mock-infected CPK and MDBK cells, the slow-migrating bands
of EF-1 protein observed in Vero and CRFK cells were barely detectable, whereas the slow-migrating bands of EF-1 protein were
prominent in cells infected with PRV(Indiana) or BHV-1(LA) (Fig. 2).
These results indicate that EF-1 is commonly modified in cells
infected with representative human and nonhuman alphaherpesviruses.
To address the question of whether beta- and gammaherpesviruses cause
the modification in the migration of EF-1 associated with
hyperphosphorylation of the protein, we examined the electrophoretic mobility of EF-1 accumulating in HLF or FHK cells infected with a
human betaherpesvirus, HCMV, and an equine gammaherpesvirus, equine
herpesvirus 2 (EHV-2), respectively. As shown in Fig.
3, there was a dramatic increase in the
abundance of the highly modified form of EF-1 in cells infected with
HCMV or EHV-2. In Fig. 3B, the amount of the hypophosphorylated form of
EF-1 also increased slightly after EHV-2 infection. However, the
increase in hyperphosphorylated EF-1 after EHV-2 infection is not
due to a simple increase in the EF-1 translation products but a
consequence of modification of EF-1 induced by EHV-2 infection since
the slower-migrating band of EF-1 was barely detectable when lysate
from mock-infected cells containing a larger amount of
hypophosphorylated form of EF-1 than that from EHV-2-infected cells
was subjected to Western blotting (data not shown). We infer from these
results that the modification of EF-1 is a conserved function in
members of all subfamilies of Herpesviridae. The
evidence that EF-1 was modified in nonprimate cell lines such
as feline, porcine, bovine, and equine cells (Fig. 2 and 3) indicates
that the modification is not restricted to primate cells infected with
human herpesviruses. Rather, it is conserved phenomena in a variety of
species of mammalian cells infected with various animal herpesviruses.
|
The observation that herpesviruses of all subfamilies modify EF-1
raised the possibility that the conserved UL13 homologues of other herpesviruses are involved in the modification of the protein.
To test this hypothesis, we used the genetically engineered HSV-1
recombinants R4969 and R4970 (Fig. 1), in which the coding domains of
UL13 were replaced by a chimeric gene capable of expressing HCMV UL97 (21). As reported elsewhere
(13), the amounts of hypo- and hyperphosphorylated EF-1
in cells infected with mutant viruses lacking the UL13 gene
could not be differentiated from those of mock-infected cells.
Therefore, if HCMV UL97 protein were involved in the
modification of EF-1, the amount of the modified form of EF-1
would increase after infection with R4969 and R4970. In this series of
experiments, HLF cells were harvested 24 h after mock infection or
infection with wild-type virus or mutant viruses, solubilized,
electrophoretically separated in a denaturing gel, transferred to a
nitrocellulose sheet, and reacted with the antibody to EF-1. The
results were as follows.
(i) As reported previously (13), in mock-infected cells, the
hypophosphorylated form of EF-1 is dominant, whereas the amount of
the hyperphosphorylated form of the protein increased after infection
with wild-type viruses (Fig. 4, lanes 2 and 5). The electrophoretic pattern of EF-1 extracted from
mock-infected cells (lane 1) could not be differentiated from those
observed for the protein extracted from cells infected with
UL13 deletion viruses (lanes 3 and 6). Furthermore, the
wild-type virus phenotype was restored in cells infected with the
recombinant R7358, in which the UL13 sequence had been
repaired (lane 8).
|
TK, thymidine kinase gene deleted; TKR, thymidine
kinase gene repaired; UL97++, UL97 gene
overexpressed.
(ii) In cells infected with
UL13
/UL97+ viruses
(Fig. 4, lanes 4 and 7), the electrophoretic pattern of EF-1 forms
was clearly differentiated from those of cells infected with
UL13 deletion mutants and mock-infected cells. The amount
of the hyperphosphorylated form of EF-1 significantly increased in
cells infected with
UL13/UL97+ viruses
compared to that in mock-infected cells or cells infected with
UL13 deletion mutant viruses, indicating that
UL97 conferred on the recipient
UL13 virus the capacity to modify EF-1.
The pattern of EF-1 in cells infected with
UL13/UL97+ viruses
was quite similar to that observed in cells infected with wild-type
HCMV (Fig. 3A). These results indicate that the posttranslational
modification of EF-1 is mediated by HCMV UL97.
Phosphorylation of proteins by protein kinase is a major strategy
employed by eukaryotic cells to regulate cellular function, including
transcription, translation, protein degradation, etc. (4).
Viruses use a similar strategy, both to regulate their own replicative
processes and to modify cellular proteins to suite their needs. Our
knowledge regarding the requirements of herpesviruses with respect to
host biosynthetic processes depends in part on the identification of
cellular proteins modified by viral protein kinases and on elucidation
of the functions altered by the phosphorylation. We should note that
the original observation that HSV-1 protein kinase phosphorylates
EF-1 should, in retrospect, have come as no surprise, since protein
synthesis is the key to viral replication and yet the translation of
mRNA seems immune to viral interference.
The hypothesis we have attempted to test stems from the observation
that the cellular translation factor, EF-1 is hyperphosphorylated by
the HSV-1 UL13 protein kinase and the evidence that
homologues of the UL13 gene are present in the genomes of
members of all three subfamilies of herpesviruses (1, 30).
Since protein kinases in general recognize specific substrates,
the question arose whether other subfamilies of herpesviruses possess
the ability to induce hyperphosphorylation of EF-1 and whether
homologues of UL13 mediate the modification of the
translation factor. The salient features of our results are as follows.
(i) Alpha-, beta-, and gammaherpesviruses commonly induce the
posttranslational modification of EF-1 associated with
hyperphosphorylation of the protein. Infection of various
mammalian cells with alphaherpesviruses (HSV-2, FHV-1, PRV,
and BHV-1), betaherpesvirus (HCMV), and gammaherpesvirus (EHV-2)
induced accumulation of the slow-migrating form of EF-1 in various
mammalian cells susceptible to these viruses. These results indicate
that the modification of EF-1 in various species of mammalian cells
is a conserved function expressed by all herpesviruses and by
extension, that EF-1 plays a crucial role in replication of the viruses.
(ii) The UL97 protein of HCMV mediates the
posttranslational modification of EF-1. The electrophoretic profiles
of EF-1 from cells infected with the
UL13/UL97+ viruses
were different from those of cells infected with the parent
UL13 viruses. Although the UL97
protein has long been thought to be a protein kinase because it has the
motifs associated with protein kinases, the only available information
of UL97 acting as a protein kinase is the evidence that it
mediated the phosphorylation HSV-1 proteins when inserted into a
HSV-1 genome (21) and that it phosphorylates itself
(8). This report shows the first evidence that
UL97 can also mediate the posttranslational modification that is involved in the phosphorylation of natural proteins except for
UL97 itself. Although we have not demonstrated that
UL97 directly phosphorylated EF-1, this is highly likely
in light of the homology of UL97 and UL13
proteins. By extension, UL13 homologues of all herpesvirus
subfamilies may be responsible for the posttranslational modification
of EF-1.
The significant new contribution of this report is the observation that
the modification of EF-1 is a specific, conserved objective of
herpesviruses belonging to all three subfamilies of herpesvirus family
and not merely that of HSV-1. This observation eliminates the slim
possibility that UL13 by chance retained the motif
necessary to bind and phosphorylate EF-1. Our results indicate that
EF-1 is of universal importance in herpesvirus infection. Although
the physiological role of the posttranslational modification of EF-1
by herpesvirus infection remains to be determined, it is conceivable
that the modification is beneficial to viral replication and is
therefore associated with activation of higher level of protein
synthesis. Further experiments to unveil the direct significance of the EF-1 hyperphosphorylation are of interest and are currently under way.
| |
ACKNOWLEDGMENTS |
|---|
We thank T. Mikami for providing CRFK cells and FHV-1(C7301) strain, and H. Ohtsuka for providing CPK and MDBK cells and PRV(Indiana) and BHV-1(LA) strains.
The work at Tokyo Medical and Dental University was supported in part by grants from the Ministry of Education, Science, Culture and Sport of Japan and the Japan Health Science Foundation. Y.K. was supported by a grant from the Ichiro Kanehara Foundation. The work at the University of Chicago was aided by grants from the National Cancer Institute (CA47451, CA71933, and CA78766) and the U.S. Public Health Service.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Tumor Virology, Division of Virology and Immunology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Phone: 81-3-5803-5814. Fax: 81-3-5803-0241. E-mail: hirai.creg{at}mri.tmd.ac.jp.
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Journal of Virology, May 1999, p. 4456-4460, Vol. 73, No. 5
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Arii, J., Uema, M., Morimoto, T., Sagara, H., Akashi, H., Ono, E., Arase, H., Kawaguchi, Y.
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