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Journal of Virology, October 1999, p. 8867-8872, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Strong Selective Pressure for Evolution of an Epstein-Barr Virus
LMP2B Homologue in the Rhesus Lymphocryptovirus
Pierre
Rivailler,
Carol
Quink, and
Fred
Wang*
Department of Medicine, Brigham and Women's
Hospital, Harvard Medical School, Boston, Massachusetts 02115
Received 11 May 1999/Accepted 15 July 1999
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ABSTRACT |
Latent membrane protein 2B (LMP2B) is expressed during latent
Epstein-Barr virus (EBV) infection, but little is known about its role.
The goal of this study was to determine whether an LMP2B homologue is
conserved in the rhesus monkey lymphocryptovirus (LCV). Both rhesus LCV
LMP2A and LMP2B genes were cloned and sequenced. The rhesus LCV LMP2B
gene is positionally conserved, and the EBNA-2 responsiveness and the
bidirectional nature of the LMP1-LMP2B promoter have also been
functionally conserved. However, this region of the genome encoding the
LMP1, LMP1-LMP2B promoter, and LMP2B first exon demonstrates the most
dramatic nucleotide sequence divergence between human and nonhuman LCV
observed to date. Evolution of the rhesus LCV LMP2B promoter and
transcript despite the dynamic nature of this genomic region reflects
strong selective pressure for a yet-to-be-identified LMP2B function.
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TEXT |
Latent membrane protein 2B (LMP2B)
is one of the three membrane proteins expressed during latent
Epstein-Barr virus (EBV) infection (for a review, see reference
17). LMP2B is also expressed in EBV-related
malignancies (for reviews, see references 2 and
29), but the role of LMP2B in EBV infection and
pathogenesis in vivo remains unknown. The LMP2B gene is closely related
to the LMP2A gene. They share eight of nine exons and are identical except for their unique first exons (20, 28). Whereas the first exon of LMP2A encodes a 119-amino-acid cytoplasmic domain, the
LMP2B first exon is noncoding. LMP2B translation initiates from an ATG
codon at the beginning of the second exon. Thus, LMP2B is essentially a
deletion mutant of LMP2A consisting of the last 379 amino acids encoded
in the common second through ninth exons. Since the LMP2B gene is
located immediately upstream of the LMP1 gene and is transcribed in the
opposite direction as LMP1, this region serves as a bidirectional
promoter for both LMP1 and LMP2B (19, 28).
To date, reports of significant functional activity for the LMP2
proteins have been limited to LMP2A and the presence of the unique
LMP2A first exon. Tyrosine residues in the LMP2A first exon are
important for interaction with and constitutive phosphorylation by syk
and lyn protein tyrosine kinases (PTKs) (8, 24). B cells
immortalized with LMP2A-deleted EBV are more sensitive to B-cell
receptor cross-linking and induction of lytic cycle infection (24,
25). Since B-cell receptor activation and src kinase activation
can induce EBV reactivation (4, 30), the interaction of
LMP2A with these PTKs is likely to be important for inhibiting lytic
cycle reactivation and maintaining latent infection in EBV-infected cells. Neither LMP2 gene is required for EBV-induced B-cell
immortalization in vitro, indicating that the LMP2A interaction with
src kinases is not required for growth transformation (22,
23). As LMP2B lacks the amino terminal cytoplasmic domain, LMP2B
is unlikely to interact with PTKs and to have similar effects on B-cell
receptor signal transduction.
The lack of obvious functional activity, the noncoding nature of the
first exon, and the unusual bidirectional nature of the LMP2B promoter
raise the possibility that the evolution of LMP2B might have been a
fortuitous event. Other herpesviruses that naturally infect Old World
nonhuman primates have evolved similarly and are classified in the same
lymphocryptovirus (LCV) subgroup as EBV (for reviews, see references
1 and 5). These simian LCVs have
similar B-cell immortalizing properties in vitro and similar
pathogenesis in vivo as EBV (10, 26). Studies from our
laboratory and others indicate that homologues for latent infection
nuclear proteins (EBNA-LP, -1, -2, -3A, -3B, and -3C) and membrane
proteins (LMP1 and LMP2A) have been conserved in baboon and rhesus LCVs
(6, 7, 15, 21, 32). Interestingly, there was no evidence for
an LMP2B transcript on Northern blots of RNA from baboon LCV-infected
cells probed with a baboon LCV LMP2A cDNA probe (6). To test
whether the LMP2B gene was an unusual evolutionary event restricted to
EBV, we examined whether the rhesus LCV encoded both LMP2A and LMP2B homologues.
LMP2A is positionally and structurally conserved in rhesus
LCV.
The putative LMP2A first exon was sequenced from the
previously published rhesus LCV DNA fragment, RE1 (7). The
sequence of a potential LMP2A ninth exon was derived from a 2.5-kb
BamHI DNA fragment (CD1PR1) which was subcloned from a
rhesus LCV cosmid clone (RcosCD1) by cross-hybridization with an EBV
LMP2A cDNA probe. Reverse transcription (RT)-PCR amplification with a
5' primer in the LMP2A first exon and a 3' primer in the putative LMP2A
ninth exon revealed a 1.9-kb product from rhesus LCV-infected B-cell
RNA. The nucleotide sequence of the 1.9-kb RT-PCR product from four
independent clones confirmed that the transcript was homologous to the
baboon LCV and EBV LMP2A transcripts (62 and 66% nucleotide homology,
respectively; Fig. 1A).
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FIG. 1.
(A) Nucleotide and amino acid sequence of the rhesus LCV
LMP2A cDNA. RT-PCR was done with 5' primer E1A
(5'-GGAATCCACCTCCTTACG-3') and 3' primer E9
(5'-GTGCTAATTTCGTGAACCCC-3'). The sequence was derived from
both strands from four independent clones (GenBank accession no.
AF148640). (B) Comparison of rhesus LCV, EBV, and baboon LCV LMP2A
protein sequences. :, amino acid identity; ., amino acid similarity.
The hydrophobic transmembrane domains (underlined) were identified with
the SOSUI program (3a). Phosphotyrosine motifs already
reported to be involved in the function of EBV LMP2A (ITAM, PPPY motif,
YEE motif) are starred.
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Translation of the rhesus LCV LMP2A cDNA revealed an open reading frame
encoding 495 amino acids with 57% amino acid identity
to the baboon
LCV and EBV LMP2A (Fig.
1B). The 12 transmembrane
domains are well
conserved. The amino-terminal cytoplasmic domain
encoded by the LMP2A
first exon and deduced from genomic DNA and
multiple RT-PCR clones is
more divergent (38% amino acid identity
to baboon LCV and EBV LMP2A).
However, important tyrosine residues
are conserved in rhesus LCV
LMP2A with an ITAM-like motif (Y73
and Y85), a conserved tyrosine
residue at position 113, and two
PPPY motifs (positions 59 to 62 and 99 to 102) (Fig.
1B). Conservation
of these motifs is consistent with an
important role for LMP2A
interaction with src kinases in the
pathogenesis of human and
nonhuman LCV
infection.
Rhesus LCV LMP2A cDNA was used as a probe to detect LMP2A and potential
LMP2B transcripts on Northern blots with RNA from
rhesus LCV-infected B
cells (Fig.
2). Whereas the EBV LMP2A
cDNA
detected both LMP2A and LMP2B transcripts of 2.3 and 2 kb,
respectively,
in EBV-infected B-cell RNA (B95-8 [
28]),
the rhesus LCV LMP2A
cDNA detected only one 2.2-kb band in rhesus
LCV-infected B-cell
RNA (194LCL). Similarly, the baboon LCV LMP2A cDNA
detected only
a single band in blots with baboon LCV-infected B-cell
RNA as
previously reported (S594 [
6]). The detection
of only a single
band on Northern blots may be consistent with
similarly sized
LMP2A and LMP2B transcripts, lower abundance of LMP2B
transcripts,
or a lack of LMP2B transcripts in the simian LCV-infected
B cells.
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FIG. 2.
LMP2A and LMP2B expression on Northern blot of EBV-,
baboon LCV-, and rhesus LCV-infected cell RNA. Total RNA (5, 10, or 20 µg) from EBV-negative cells (BJAB) and from cells infected with EBV
(B95.8), baboon LCV (S594), and rhesus LCV (194LCL) were hybridized
with EBV LMP2A cDNA, baboon LCV LMP2A cDNA, and rhesus LCV LMP2A cDNA.
Migration of 28S and 18S rRNAs are shown.
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LMP2B first exon is positionally conserved despite divergence
between rhesus LCV and EBV LMP1-LMP2B promoter regions.
To test
whether a rhesus LCV LMP2B first exon was positionally conserved, we
cloned and sequenced 563 bases of the LMP1 upstream region (Fig.
3). Surprisingly, the rhesus LCV LMP1
promoter is not well conserved with the EBV LMP1 promoter (27%
nucleotide homology). This is significantly different from other latent
infection promoters from rhesus and baboon LCVs (Table
1). Despite the poor sequence homology,
RBP-J
/CBF-1 (12, 13) and PU.1/Spi1 (16, 18)
binding sites important for LMP1 transcriptional regulation have been
conserved (Fig. 3). Interestingly, the rhesus LCV LMP1 promoter
contains only one RBP-J/CBF-1 binding site, compared to two in EBV,
and both the RBP-J/CBF-1 and PU.1/Spi1 binding sites are located on
the opposite strand as compared to the EBV LMP1 promoter. These
findings suggest that despite the high degree of genetic evolution in
this region, there is strong selective pressure for conserving
important transcriptional regulatory motifs.
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FIG. 3.
(A) Comparison of rhesus LCV and EBV LMP1 promoter
sequences. The rhesus LCV LMP1 promoter was amplified with a 5' primer
Rh1 (5'-AACCAGACCTTGCCAC-3') and a 3' primer TR from the EBV
sequence at nucleotide 170,012 (5'-TCTGAAATTCCCATATCCGC-3')
and both strands were sequenced from three independent clones
(GenBank accession no. AF148641). PU.1/Spi1 (AAAGGGGAAGT)
binding sites are double underlined and RBP-J/CBF-1 binding
sites are boxed. Note that PU.1/Spi1 and RBP-J/CBF-1 sites within
rhesus LCV LMP1 promoter are on the opposite DNA strand as compared to
the EBV LMP1 promoter. Primers (1 to 7) used to amplify a rhesus LCV
LMP2B transcript are indicated. The end of the rhesus LCV LMP2B first
exon is denoted by an arrowhead. :, nucleotide identity. (B) LMP2A and
LMP2B RT-PCR from rhesus LCV-infected cell RNA. RT-PCR amplification
for LMP2B was done with E2r (5'-GTAACAATGCCGACGAGGAT-3') and
one of seven primers (1 to 7) covering the 500-bp upstream rhesus LCV
LMP1 translational initiation site. RT-PCR amplification for LMP2A was
done with primers E2r and E1A (5'-GGAATCCACCTCCTTACG-3'). No
amplification is detected if no RT is added in the reaction ( RT). (C)
Control PCR amplifications from a synthetic DNA amplicon or LMP2A cDNA
clone. PCR was done with the same primers as described for panel B.
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No obvious LMP2B TATA box was found in the LMP1 upstream region as is
the case for EBV LMP2B. Therefore, we designed a series
of primers in
the LMP1 promoter region in order to identify potential
rhesus LCV
LMP2B transcripts by RT-PCR amplification. Seven primers
(designated 1 to 7; Fig.
3A) were paired with a 3' primer in the
second exon of LMP2A
(E2r) for RT-PCR amplification of RNA from
rhesus LCV-infected B cells.
As shown in Fig.
3B, an RT-PCR product
was obtained when primers 4, 5, and 6 were paired with E2r. No
product was detected in the absence of
RT, and no product was
obtained when primers 1, 2, 3, or 7 were paired
with E2r even
though these primer combinations were able to amplify a
product
from an artificial DNA construct (Fig.
3C). Sequencing of the
RT-PCR products obtained with the primer pairs of 4, 5, and 6
with E2r
confirmed that the splice donor site was at nucleotide
476 relative
to the LMP1 translational initiation site and the
splice acceptor site
in the second exon was identical to LMP2A.
Longer RT-PCR products (1.5 to 1.6 kb) were also obtained with
primers 4, 5, and 6 with a 3' primer
in the LMP2A ninth exon,
suggesting that the rhesus LCV LMP2B shares
exons two through
nine of LMP2A (data not shown). Finally, the RT-PCR
results also
suggest that the 5' end of the LMP2B transcript is between
primers
3 and 4, approximately
337 to
361 nucleotides upstream of
the
LMP1 translational initiation site. In that case, the LMP2B first
exon (110 bp) should be shorter than the LMP2A first exon (350
bp),
suggesting that the failure to detect an LMP2B transcript
on Northern
blots is due to a much lower level of expression for
rhesus LCV LMP2B
than for
LMP2A.
Transcriptional regulation of the LMP1-LMP2B bidirectional promoter
is conserved in rhesus LCV.
Reporter constructs were made to test
whether the bidirectional nature and EBNA-2 responsiveness of the LMP1
promoter were functionally conserved in rhesus LCV. EBV and rhesus LCV
DNA fragments containing the LMP1 promoter were cloned in either
direction relative to a luciferase reporter gene (Fig.
4, panel I). Both EBV and rhesus LCV LMP1
promoters (parts A and C, open boxes; Fig. 4, panel II) showed three-
to sixfold activation of the reporter gene relative to the luciferase
gene alone (pGL2; Fig. 4, panel II) when transfected into EBV-negative
human B lymphoma cells. When the promoter elements were cloned in the
opposite orientation (parts B and D, open boxes; Fig. 4, panel II),
similar levels of activity were detected, indicating that the EBV and
rhesus LCV LMP1 promoters are bidirectional. To test whether EBNA-2
responsiveness had been conserved, promoter constructs were
cotransfected with an EBV EBNA-2 expression construct. EBNA-2
cotransfection increased luciferase activity of the rhesus LCV promoter
five- to sixfold in either the LMP1 or LMP2B orientation (Fig. 4, panel
II, filled boxes). The level of LMP1-LMP2B promoter activity induced by
EBNA-2 was comparable among the EBV and rhesus LCV promoters.
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FIG. 4.
Promoter analysis of EBV and rhesus LCV LMP1 promoters.
(Panel I) The LMP1 transcript, LMP2B transcript, PU.1/Spi1 and
RBP-J/CBF-1 binding sites, and terminal repeats (TR) from EBV and
rhesus LCV are shown. Luciferase reporter constructs with EBV sequences
(A and B) and rhesus LCV sequences (C and D) are shown. (Panel II)
Promoter activity of luciferase reporter constructs in EBV-negative
human B lymphoma cells in the absence (open bars) or presence (solid
bars) of EBV EBNA-2 is shown. Luciferase activity was normalized for
transfection efficiency by using a cotransfected simian virus 40 early
promoter-driven  -galactosidase expression plasmid. Results are the
averages of five independent assays, and the error bars represent the
standard deviations.
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These studies show that the LMP2B transcript, the bidirectional nature
of the LMP1-LMP2B promoter, and the EBNA-2 responsiveness
of the
bidirectional LMP1-LMP2B promoter have been conserved in
the rhesus
LCV. This end of the LCV genome is highly divergent
at the nucleotide
level from the terminal repeat, through the
LMP2B first exon-promoter
(27% homology), LMP1 gene (29%), and
LMP2A first exon (38%). The
conservation of the rhesus LCV LMP2B
promoter and transcript, despite
the dynamic nature of this genomic
region, reflects strong selective
pressure for an important but
yet-to-be-identified LMP2B function.
Since LMP2B is a deletion
mutant of LMP2A, it is possible that LMP2B
may act to modulate
LMP2A function in some manner. However, in vitro
studies to date
have revealed no evidence for an LMP2B regulatory
effect on LMP2A
function. In vivo studies with an LMP2B deleted virus
may be required
to reveal important LMP2B functions. Homologues for all
of the
EBV genes expressed during latent infection have now been
identified
in the rhesus LCV, including EBNA-1, -2, -3A, -3B, -3C, -LP,
LMP1,
LMP2A, LMP2B, and EBERs (
3,
7,
11,
14,
15). These
molecular studies add further support to and highlight the potential
utility of rhesus LCV as an important animal model for EBV
infection.
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ACKNOWLEDGMENTS |
This work was funded by grants from the Public Health Service
(CA68051 and CA65319). P.R. was a fellow of the Association pour la
Recherche sur le Cancer.
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FOOTNOTES |
*
Corresponding author. Mailing address: Channing
Laboratories, 181 Longwood Ave., Boston, MA 02115. Phone: (617)
525-4258. Fax: (617) 525-4257. E-mail:
fwang{at}rics.bwh.harvard.edu.
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Journal of Virology, October 1999, p. 8867-8872, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Jimenez-Ramirez, C., Brooks, A. J., Forshell, L. P., Yakimchuk, K., Zhao, B., Fulgham, T. Z., Sample, C. E.
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