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Journal of Virology, May 2000, p. 4425-4428, Vol. 74, No. 9
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Expression and Characterization of the Borna
Disease Virus Polymerase
Michelle Portlance
Walker,
Ingo
Jordan,
Thomas
Briese,
Nicole
Fischer, and
W. Ian
Lipkin*
Emerging Diseases Laboratory, Departments of
Neurology, Anatomy and Neurobiology, and Microbiology and Molecular
Genetics, University of California, Irvine, California 92697-4292
Received 11 October 1999/Accepted 29 January 2000
 |
ABSTRACT |
Borna disease virus is the prototype of a new family,
Bornaviridae, within the order Mononegavirales,
that is characterized by nuclear transcription, splicing, low level
replication, and neurotropism. The products of five open reading frames
predicted from the genomic sequence have been confirmed; however,
expression of the sixth, corresponding to the putative viral polymerase
(L), has not been demonstrated. Here, we describe expression and
characterization of a 190-kDa protein proposed to represent L. Expression of this protein from the third transcription unit of the
viral genome is dependent on a splicing event that fuses a small
upstream open reading frame in frame with the larger downstream
continuous open reading frame. The protein is detected by serum
antibodies from infected rats and is present in the nucleus, where it
colocalizes with the phosphoprotein. L is also shown to be
phosphorylated by cellular kinases and to interact with the viral
phosphoprotein in coimmunoprecipitation studies. These findings are
consistent with the identity of the 190-kDa protein as the viral
polymerase and provide insights and describe reagents that will be
useful for Bornavirus molecular biology and pathobiology.
| |
TEXT |
Borna disease virus (BDV)
is a nonsegmented, negative-strand RNA virus that establishes
persistent central nervous system infection and causes behavioral
disturbances in warm-blooded animals (12, 16). Notable
features of its molecular biology include replication and transcription
in the nucleus (1, 3, 5), overlap of open reading frames
(ORFs) and transcription units (2, 17), RNA splicing
(7, 19), differential use of transcription termination sites
and translation codons (17, 19), and requirements for
phosphorylation by kinases with limited distribution within the central
nervous system (20). The antigenome contains three transcription units and six ORFs (2, 6). The products of five ORFs have been described, including, from the 5' end to the 3' end
on the antigenome, the nucleoprotein (N) (13), X protein (X)
(26), phosphoprotein (P) (25), atypical
glycosylated matrix protein (gp18) (9), and type 1 membrane
glycoprotein (G) (8, 18). The sixth ORF occupies
two-thirds of the antigenome, contains motifs conserved
amongst polymerases of negative-strand RNA viruses, and is postulated
to encode the BDV polymerase (L) (2, 6); however, the
product of this ORF is not reported. Expression and characterization of
the BDV polymerase were pursued with the objective of obtaining a more
detailed understanding of BDV molecular biology.
L expression requires splicing and suppression of termination.
The third transcription unit of BDV strain V initiates at nucleotide
(nt) 1889 and terminates at either termination site 3 (T3) (nt 4505) or
T4 (nt 8855). Transcripts terminated at T3 may be spliced and
translated into either or both gp18 and G (18, 19).
Transcripts which read through T3 and terminate at T4 encode a
continuous L ORF with five potential translation initiation sites. The
AUG corresponding to strain V nt 4146 was proposed to initiate
translation of L, resulting in expression of a 170-kDa protein
(6); however, between the G ORF translation termination site
and this AUG, the predicted amino acid sequence of strain V and strain
He/80 is fully conserved, indicating that this region is likely to be
translated (strain V, nt 3704 to 4146) (Fig.
1A). Recognition of splicing in BDV
provided a mechanism for expression of the conserved sequence (nt 3704 to 4146): splicing of intron II (nt 2410 to 3703) results in fusion of
17 nt to the 5' end of the conserved sequence at nt 3704 and provides
an in-frame AUG (nt 2393) that allows utilization of the entire ORF,
encoding a protein predicted to be 190 kDa (Fig. 1A) (19).
Consistent with this model, a protein with an apparent molecular mass
of 190 kDa was precipitated by anti-L1 antisera directed against a
peptide within the conserved sequence (Fig. 1A) from lysates of strain
V-infected COS-7 cells (Fig. 1B, lane 4) and from lysates of BSR-T7
cells (BHK-21 cells stably transfected with a T7 RNA polymerase
expression plasmid) following Lipofectin (GIBCO-BRL) transfection with
pTM-L1 (Fig. 1B, lane 3). pTM-L1 expresses the entire proposed strain V
L ORF, nt 2393 to 2410 fused to nt 3704 to 8822, from an internal
ribosome entry site-containing T7 promoter plasmid (14).
Similar results were obtained with pB-L, a T7 expression plasmid which
lacks the internal ribosome entry site. pCD-L, a cytomegalovirus (CMV)
promoter plasmid, failed to produce L mRNA and/or protein. The 190-kDa
protein was also precipitated from lysates of infected COS-7 cells by
anti-L2 antisera directed against peptides distributed throughout the
remainder of the L ORF (Fig. 1A and Fig. 1B, lane 5). Neither anti-L1
nor anti-L2 antisera precipitated proteins of similar molecular weights
from lysates of noninfected cells (Fig. 1B, lanes 1 and 8) or
mock-transfected cells (Fig. 1B, lanes 2 and 7). Anti-L2 antisera did
not precipitate a smaller protein of 170 kDa from infected cell lysates
(Fig. 1B, lane 5), consistent with the size of the protein
precipitated from pTM-L2 (nt 4146 to 8822)-transfected BSR-T7 cells
(Fig. 1B, lane 6). Anti-L1 antisera failed to precipitate a protein
lacking sequence upstream of nt 4146 from lysates of pTM-L2-transfected BSR-T7 cells (Fig. 1C, lane 5), confirming the presence of the conserved sequence (nt 3704 to 4146) in the protein precipitated from
infected cell lysates.
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FIG. 1.
Detection of L in infected and transfected cells. (A)
Representation of BDV third transcription unit, indicating inserts of
L-T7 expression plasmids pTM-L1 and pTM-L2. The relative positions of
the peptides used to elicit murine antisera to L are indicated, and the
sequences are shown underneath. The cross-hatched area indicates a
region of conserved sequence predicted to be incorporated into L
(2). (B) Immunoprecipitation of 190-kDa wild-type or
recombinant L from COS-7 cells or from BSR-T7 cells, respectively, by
using anti-L1 antisera (lanes 1 to 4), anti-L2 antisera (lanes 5 to 8),
or preimmune mouse sera (lanes 9 to 12) with protein G-Sepharose
(Pharmacia). Metabolically labeled lysates (labeled with
[35S]methionine) were obtained from noninfected COS-7
cells (lanes 1 and 8), mock (vector)-transfected BSR-T7 cells (lanes 2, 7, and 12), pTM-L1-transfected BSR-T7 cells (lanes 3 and 10), infected
COS-7 cells (lanes 4, 5, and 9), or pTM-L2-transfected BSR-T7 cells
(lanes 6 and 11). (C) Immunoprecipitation of lysates from pTM-L1 (lanes
1 to 3) or pTM-L2 (lanes 4 to 6) transiently transfected BSR-T7 cells
by using preimmune mouse sera (lanes 1 and 6), anti-L2 antisera
(reactive with sequence common to pTM-L1 and pTM-L2) (lanes 2 and 4),
or anti-L1 antisera (reactive within the conserved sequence [nt 3704 to 4146] of L unique to pTM-L1) (lanes 3 and 5). The filled arrows
indicate the position of L initiating at the AUG at nt 2393; the open
arrows indicate the position of L initiating at the AUG at nt 4146. Immunoprecipitation analysis was done by SDS-7.5% PAGE.
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Infected rats have antibodies reactive with L.
As an
independent test for expression of L in vivo, Lewis rats with clinical
signs of Borna disease were bled 2 and 4 months after intracranial
infection and assayed for the presence of serum antibodies to
recombinant L. Sera obtained from two infected rats precipitated L from
metabolically [35S]methionine-labeled BSR-T7 cells that
were transiently transfected with pTM-L1 (Fig. 2, lanes 2 and
3). Signal was higher in samples precipitated using 4-months-postinfection sera, suggesting a higher titer of antibodies to L. Sera from noninfected rats did not
precipitate L (Fig. 2, lane 4).
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FIG. 2.
Sera from BDV strain V-infected rats recognizes
recombinant 190-kDa L. Metabolically labeled lysates obtained from
pTM-L1-transfected BSR-T7 cells (lanes 1 to 4) or mock
(vector)-transfected BSR-T7 cells (lanes 5 to 8) were
immunoprecipitated using anti-L1 antisera (lanes 1 and 5), rat sera 2 months (lanes 2 and 6) or 4 months (lanes 3 and 7) post-BDV infection,
or noninfected rat sera (lanes 4 and 8). Immunoprecipitation analysis
was done by SDS-7.5% PAGE.
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|
L localizes to the nucleus of infected or L-transfected cells.
BDV transcribes its genome in the nucleus (1, 3, 5);
thus, if L represented the viral polymerase, it would be anticipated to
be present in the nucleus. Potential nuclear localization sequences within the L ORF have been proposed (6); however, other BDV proteins also contain nuclear localization sequences (10,
15, 21, 23) and might facilitate nuclear localization of L
through protein-protein interaction-mediated transport. The
distribution of wild-type and recombinant L was examined in strain
V-infected COS-7 (Fig. 3a) and BSR-T7
(Fig. 3d) cells and in noninfected BSR-T7 cells transiently transfected
with pTM-L1 (Fig. 3b). In all three systems, L was predominantly
nuclear, as determined by immunofluorescence analysis with anti-L1
antisera, indicating that the protein is imported into the nucleus in
the absence of other viral proteins.
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FIG. 3.
Localization of L and of L with P by indirect
immunofluorescence in infected COS-7 or BSR-T7 cells or in noninfected,
transfected BSR-T7 cells. (a) Infected COS-7 cells, anti-L1 antisera;
(b) pTM-L1-transfected BSR-T7 cells, anti-L1 antisera; (c) noninfected
COS-7 cells, anti-L1 antisera; (d) infected BSR-T7 cells, anti-L1
antisera; (e) infected BSR-T7 cells, anti-P antisera; (f) infected
BSR-T7 cells, anti-L1 and anti-P antisera; (g) pTM-L1- and
pcDNA-P-transfected BSR-T7 cells, anti-L1 antisera; (h) pTM-L1- and
pcDNA-P-transfected BSR-T7 cells, anti-P antisera; (i) pTM-L1- and
pcDNA-P-transfected BSR-T7 cells, anti-L1 and anti-L2 antisera; (j)
noninfected, nontransfected BSR-T7 cells, anti-L1 antisera; (k)
noninfected, nontransfected BSR-T7 cells, anti-P antisera.
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L interacts with the BDV P protein.
Polymerases of
rhabdoviruses and paramyxoviruses interact with viral phosphoproteins
to form the active polymerase complex (24). Previous studies
have shown that BDV P interacts with BDV N and BDV X (22).
To assess whether BDV P might also interact with L,
coimmunoprecipitation and colocalization experiments were performed.
Colocalization experiments were performed in infected COS-7 cells (data
not shown) or BSR-T7 cells (Fig. 3d to f) or in BSR-T7 cells
transiently transfected for coexpression of L and P (Fig. 3g to i).
Whereas in infected cells both proteins colocalized in the nucleus, in
transfected cells both proteins colocalized predominantly in the
cytoplasm. This shift in localization may result from the
overexpression of L-P complexes in the absence of other viral factors
within transfected cells. Coimmunoprecipitation experiments were
performed with metabolically labeled lysates (labeled with
[35S]methionine) from infected COS-7 cells or BSR-T7
cells transfected with pTM-L1 (L expression) and/or pcDNA-P (P
expression), and polyclonal rabbit antisera to P or anti-peptide
antisera (anti-L1 or anti-L2). Anti-P antisera coprecipitated L with P
from lysates of infected cells (Fig. 4, lanes
11) or from lysates of
cells transfected for expression of both L and P (Fig. 4, lanes 7). A
carboxyl-terminal deletion mutant of L (deletion of 941 carboxyl-terminal amino acids; pTM-L
C) also coprecipitated with P
(Fig. 4, lanes 8); however, L was not coprecipitated from lysates of
cells transfected for expression of L and a phosphorylation-deficient
mutant of P (pcDNA-Pmut), in which all known phosphorylation sites
(20) have been mutated to alanine (Fig. 4, lanes 5).
In concert, these results indicate that the interaction of P with
L involves phosphorylation of P and implicate the amino-terminal half
of L in this interaction. The inability of anti-L1 (Fig. 4, lanes 6 and
10) and anti-L2 (data not shown) to coprecipitate P together with L is
consistent with a model where the major epitopes detected by anti-L1
and anti-L2 are obscured by binding of L to P; however, sites of L-P interaction have not yet been mapped.
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FIG. 4.
Coimmunoprecipitation of L with P. Metabolically labeled
lysates obtained from infected COS-7 cells or noninfected BSR-T7 cells
transfected with pTM-L1 (L expression) or pcDNA-P (P expression) were
immunoprecipitated by anti-L1 or anti-P antisera. Samples were split
and analyzed by SDS-7.5% PAGE for L (A) and by SDS-10% PAGE for
P (B). Lanes: 1, infected COS-7 cells, preimmune sera; 2, pTM-L1
transfected BSR-T7 cells, anti-P antisera; 3, pcDNA-P transfected
BSR-T7 cells, anti-L1 antisera; 4, pTM-L1 and pcDNA-P cotransfected
BSR-T7 cells, preimmune sera; 5, pTM-L1 and pcDNA-Pmut cotransfected
BSR-T7 cells, anti-P antisera; 6, pTM-L1 and pcDNA-P cotransfected
BSR-T7 cells, anti-L1 antisera; 7, pTM-L1 and pcDNA-P cotransfected
BSR-T7 cells, anti-P antisera; 8, pTM-Lc and pcDNA-P cotransfected
BSR-T7 cells, anti-P antisera; 9, pTM-L1 transfected BSR-T7 cells,
anti-L1 antisera; 10, infected COS-7 cells, anti-L1 antisera; 11, infected COS-7 cells, anti-P antisera; 12, pcDNA-P-transfected BSR-T7
cells, anti-P antisera.
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L is phosphorylated.
The sequence of L contains at least 40 potential phosphorylation sites (11). Because
phosphorylation is implicated in regulating the activity of catalytic
enzymes (4), including polymerases of negative-strand RNA
viruses, phosphorylation of BDV L was investigated. Metabolically
labeled extracts (labeled with [32P]orthophosphate)
of infected BSR-T7 cells and noninfected BSR-T7 cells transfected
with pTM-L1 were immunoprecipitated with anti-L1 antisera and size
fractionated by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (SDS-PAGE). A 190-kDa radiolabeled protein was present
in both infected and transfected cells, consistent with phosphorylation
of L by cellular kinases (Fig. 5, lanes 1 and
2).
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FIG. 5.
Phosphorylation of wild-type and recombinant L. Metabolically labeled lysates obtained from infected BSR-T7 cells
(lanes 1 and 4), pTM-L1-transfected BSR-T7 cells (lane 2), or mock
(vector)-transfected BSR-T7 cells (lane 3) were immunoprecipitated by
anti-L1 antisera (lanes 1 to 3) or preimmune mouse sera (lane 4).
Immunoprecipitation analysis was done by SDS-7.5% PAGE.
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|
The characteristics of the 190-kDa protein described here, including
size, position on the viral antigenome, presence of motifs
consistent
with polymerases of negative-strand RNA viruses, nuclear
localization,
potential for phosphorylation, and colocalization
and interaction with
the BDV phosphoprotein provide indirect but
strong support for the
conclusion that it is the BDV polymerase.
Although native L and its
corresponding mRNA appear to be present
only at low levels in infected
cells, we have established methods
for overexpression of L that afford
unprecedented opportunities
for pursuing functional assays and reverse
genetic
systems.
| |
ACKNOWLEDGMENTS |
We are grateful to Xi Yu Jia for helpful discussions, to Bernard
Moss for the gift of the plasmid pTM1, and to Karl-Klaus Conzelmann for
helpful comments and the gift of the BSR-T7 cell line.
This work was supported by grant NS29425 from the National Institutes
of Health.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Emerging
Diseases Laboratory, 3101 Gillespie Neuroscience Building, University
of California, Irvine, CA 92697-4292. Phone: (949) 824-6193. Fax: (949)
824-1229. E-mail: ilipkin{at}uci.edu.
| |
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Journal of Virology, May 2000, p. 4425-4428, Vol. 74, No. 9
0022-538X/00/$04.00+0
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