Vaccinia Virus Semaphorin

4 Pages·2000·0.209 MB·English

by  McFadden G., Moyer R.

Vaccinia Virus
Semaphorin
Grant McFadden1,* and Richard Moyer2
1The John P. Robarts Research Institute and Department of Microbiology and Immunology,
The University of Western Ontario, 1400 Western Road, London, Ontario, N6G2V4, Canada
2Department of Molecular Genetics and Microbiology, University of Florida College of Medicine,
PO Box 100266, Gainesville, FL 32610-0266, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.03019.
SUMMARY Structure
Certain poxviruses express a member of the sema- A39R is a contiguous gene lacking introns.
phorin superfamily, which are a large group of cel-
lular proteins that were first characterized in nervous
tissue as regulators of guidance of sensory neurons, Main activities and
butmembersprobablyhaveimmunomodulatoryroles pathophysiological roles
as well. The vaccinia virus semaphorin is encoded by
the A39R gene (in strain Copenhagen) and is ex-
The protein binds to human monocytes and causes
pressed as a secreted protein that binds to a cellular
large cellular aggregates, suggesting induction of cell
receptor called VESPR (virus-encoded semaphorin
surface activation antigens. Treatment of monocytes
protein receptor), but the biological role of this
withA39RleadstotheinductionofCD54(ICAM-1).
protein has yet to be defined.
Human monocyte cultures incubated with A39R
induce production of the proinflammatory cytokines
BACKGROUND IL-8 and perhaps IL-6.
Discovery
GENE AND GENE REGULATION
Supernates from cells infected with vaccinia virus
Accession numbers
(Lister strain) in serum-free media were analyzed by
two-dimensional gel electrophoresis. A novel protein
of 55kDa (pI of 10) was noted. N-terminal sequ- M35027
encingshowedidentitywithaminoacids15–24ofthe
A39R ORF of the sequence vaccinia Copenhagen
Chromosome location
strain. Subsequent analysis revealed the similarity to
semaphorins (Comeau et al., 1998).
ThegeneislocatedintheHindIIIA(largestfragment
resulting from HindIII digestion of viral DNA) frag-
Alternative names
ment of the vaccinia Copenhagen genome. The
designation ‘R’ refers to the direction of transcrip-
A39R ORF (vaccinia Copenhagen) tion, which is from left to right.
1434 Grant McFadden and Richard Moyer
Regulatory sites and corresponding GenPept:
335517
transcription factors
Sequence
Expression of the A39R gene is proposed to be late
and dependent on viral DNA replication, because of
thepresenceofthelatepoxviruspromoterTAAATG See Figure 1.
motif and the presence of a single early transcription
termination signal (TTTTTNT) within the gene.
Description of protein
Cells and tissues that
express the gene The protein contains a cleaved 14 amino acid N-
terminal signal sequence. Hence the first 14 amino
acids are absent in the secreted protein. There are
Vaccinia virus (Copenhagen) expresses a 403 amino
several potential N-linked glycosylation sites. The
acid protein, whereas the corresponding ORF in
protein is a member of the semaphorin family.
vacciniaWRis441aminoacidsduetoanN-terminal
Semaphorins typically contain an N-terminal signal
extension of 38 amino acids. A related sequence is
sequence followed by a large (500 amino acid) region
found in variola (India) virus but is interrupted to
of loosely conserved amino acids called a ‘Sema’
comprise three open reading frames: variola ORFs
domain (Kolodkin et al., 1993).
A42 (amino acids 1–71), A43 (amino acids 146–237),
and A44 (amino acids 262–398). A segment of the
vaccinia virus Copenhagen A39R gene (comprising Important homologies
amino acids 76–110) is found within a molluscum
contagiosum ORF (MC163R) of 620 amino acids.
Interestingly, the prototypic members of the Sema
family are cellular proteins originally described as
being involved in neuronal development in grass-
PROTEIN
hoppers (Kolodkin et al., 1992) and in avian growth
cone guidance development (Luo et al., 1993).
Accession numbers
However, one of the semaphorins (CD100) and the
mouse homolog Sema G serve to regulate immune
GenBank: function (Hall et al., 1996; Elhabazi et al., 1997).
M35027 CD100, an 862 amino acid protein, is expressed on
Figure 1 Amino acid sequence of vaccinia semaphorin.
Vaccinia Virus Semaphorin 1435
Figure 2 A ‘best fit’ alignment of the vaccinia (VAC) (403 amino acid) and alcelaphine
herpesvirus type 1 (AHV) (643 amino acid) semaphorins. The two proteins share only 29%
amino acid identity.
the surface of hematopoietic cells and antibodies RECEPTOR UTILIZATION
against CD100 affect T cell activity. The alcelaphine
herpesvirus type 1 (AHV) (Ensser and Fleckenstein,
One receptor for the vaccinia A39R protein has been
1995)also encodesasemaphorin (Langeet al.,1998).
isolatedfromcellsoflymphoidorigin(Comeauetal.,
AHV is the causative agent of malignant catarrhal
1998). This virus-encoded semaphorin protein recep-
fever in ruminants. The AHV protein is considerably
tor (VESPR) is a 1568 amino acid (200kDa) type I
longer (643 amino acids) than the vaccinia protein
transmembrane glycoprotein, which is a member of
(403aminoacids).TherelationshipbetweentheAHV
theplexinfamily.Theplexinfamilymembersaretypi-
and vaccinia proteins is shown in Figure 2.
cally type I membrane proteins and were originally
Both the vaccinia and AHV proteins bind to the
identified in the Xenopus nervous system. The extra-
virus-encoded semaphorin protein receptor (VESPR)
cellular segments of plexins possess three internal
isolated (Comeau et al., 1998) as the receptor for the
repeatsofcysteineclustersthatarehomologoustothe
vaccinia protein. While both proteins bind to the
cysteine-rich domain of the c-met proto-oncogene
VESPRreceptorwithhighavidity,thevacciniaprotein
proteinproduct.Plexinsareinvolvedincelladhesion.
is the preferred ligand.
Homologs of this plexin family have been isolated
frommouse,human,andXenopustissues,althoughas
yet no ligands have been identified. VESPR contains
Posttranslational modifications
anN-terminalsignalsequence,withapotentialcleav-
age site between amino acids 34 and 35. There are 24
The A39 ORF contains an N-terminal signal sequ- putative N-linked glycosylation sites. The protein
enceandcleavagesitebetweenaminoacids14and15. contains a transmembrane sequence at amino acids
There are also several potential N-glycosylation sites 945–965. The extracellular domain of VESPR con-
at amino acids 53–56, 126–129, and 240–243, as well tains a region of amino acid homology that is also
as several potential myristolylation sites. foundwithinthesemaphorinproteinsthemselves(the
1436 Grant McFadden and Richard Moyer
Sema domain). This homology is located at amino (1998). A poxvirus-encoded semaphorin induces cytokine pro-
acids 380–482 of the VESPR sequence and corre- duction from monocytes and binds to a novel cellular sema-
phorinreceptor.VESPRImmunity8,473–482.
spondstoaC-terminal100aminoacidportionofthe
Elhabazi,A.,Lang,V.,Herold,C.,Freeman,F.J.,Bensussan,A.,
semaphorin domain. VESPR is found in a variety of
Boumsell,L.,andBismuth,G.(1997).Thehumansemaphorin-
tissues and cells including B and T cells from peri- like leukocyte cell surface molecule CD 100 associates with a
pheral blood, monocytes and dendritic cells. serinekinaseactivity.J.Biol.Chem.272,23515–23520.
Ensser, A., and Fleckenstein, B. (1995). Alcelaphine herpesvirus
type 1 has a semaphorin-like gene. J. Gen. Virol. 76, 1063–
1067.
IN VITRO ACTIVITIES
Hall, K. T., Boumsell, L., Schultze, J. L., Boussiotis, V. A.,
Dorfman,D.M.,Cardoso,A.A.,Bensussan,A.,Nadler,L.M.,
In vitro findings and Freeman, G. J. (1996). Human CD100, a novel leukocyte
semaphorin that promotes B-cell aggregation and differentia-
tion.Proc.NatlAcad.Sci.USA93,11780–11785.
Thevacciniasemaphorinbindstomonocytesthrough Kolodkin, A. L., Matthes, D. J., O’Connor, T. P., Patel, N. H.,
interaction with VESPR and causes them to aggre- Admon,A.,Bentley,D.,andGoodman,C.S.(1992).Fasciclin
IV:Sequence,expressionandfunctionduringgrowthconegui-
gate.CD54expressionisupregulatedandsynthesisof
danceinthegrasshopperembryo.Neuron9,831–845.
IL-8 and IL-6 is induced. Both the AHV semaphorin
Kolodkin,A.L.,Matthes,D.J.,andGoodman,C.S.(1993).The
andcellularCD100alsocausemonocyteaggregation.
semaphorin genes encode a family of transmembrane and
secretedgrowthconeguidancemolecules.Cell75,1389–1399.
Lange,C.,Liehr,T.,Goen,M.,Gebhart,E.,Fleckenstein,B.,and
References Ensser, A. (1998). New eukaryotic semaphorins with close
homologytosemaphorins ofDNA viruses. Genomics 51,340–
350.
Comeau, M. R., Johnson, R., DuBose, R. F., Petersen, M., Luo,Y.,Raible,D.,andRaper,J.A.(1993).Collapsin:aprotein
Gearing,P.,VandenBos,T.,Park,L.,Farrah,T.,Buller,R.M., in brain that induces the collapse and paralysis of neuronal
Cohen,J.I.,Strockbine,L.D.,Rauch,C.,andSpriggs,M.K. growthcones.Cell75,217–227.