CC Chemokine of Molluscum Contagiosum Virus

4 Pages·2000·0.141 MB·English

by  McFadden G., Moyer R.

CC Chemokine of
Molluscum Contagiosum
Virus
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, N6G 2V4, 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.2000.03018.
SUMMARY immunocompromised individuals. However, mollus-
cuminfectionsareaconcerninimmunocompromised
individualsandinparticularwithindividualssuffering
Virus-encodedmembersofthechemokinesuperfamily
fromAIDS,wheredisfiguringillnesscanresult.
ofligandshavebeendiscoveredinthegenomesofcer-
tainpoxvirusesandherpesviruses.TheMC148Rgene
ofmolluscumcontagiosumvirus,ahuman-specificpox-
Discovery
virusthatinducesbenignskinlesionswhichcanbecome
clinically serious in immunocompromised patients,
The molluscum protein, designated as MC148R
encodesforamemberoftheCCchemokinesuperfamily
(based on the open reading frame designation), was
thatcanantagonizetheactivitiesofseveralhumanCC
first recognized as a possible chemokine homolog as
chemokinestested.TheMC148Rproteinlackscertain
part of the characterization and annotation of the
aminoacidmotifsattheN-terminusthatarebelievedto
completeDNAsequenceofthevirus(Senkevichetal.,
be required for signaling from cognate chemokine
1996, 1997). Based on restriction digestion patterns,
receptors, andthisfeatureisbelievedtobeimportant
there are two distinct MCV isolates, designated as
foritsactivityasaCCchemokineantagonist.
type 1 and type 2 (Darai et al., 1986). A nearly
identical protein is encoded by both isolates.
BACKGROUND
Alternative names
Variola virus, the causative agent of smallpox, and
molluscum contagiosum virus (MCV) are the only two ORFMC148R,MCVchemokinehomolog(MCCH),
poxviruses whose infections are limited to human MC148P.
hosts.Smallpoxinfectionsaretypicallyadisseminated
disease ultimately involving many organs and tissues.
Structure
Ordinary smallpox, caused by variola major (of the
genusOrthopoxvirus)exhibitsa30%mortality.Mollus-
cumcontagiosum,belongingtoaseparategenus,causes MC148R is a contiguous gene, typical of poxviruses,
benign proliferative lesions of the skin in normal and lacking introns.
1286 Grant McFadden and Richard Moyer
Main activities and suggeststhatthegeneisexpressedearly,beforeDNA
replication (Bugert et al., 1998). A poxvirus sequence
pathophysiological roles
(TTTTTNT), typical of an early poxvirus transcrip-
tionterminationsignal,isfound40bpdownstreamof
One of the most remarkable features of molluscum the 30 translation stop codon consistent with early
contagiosum infections is the absence of inflamma-
transcription of the gene.
tory cell infiltrates within lesions that contain large
numbers of viral particles. MCCH has been shown
to block the chemotactic response of multiple subsets
PROTEIN
of leukocytes to both CC and CXC chemokines
(Krathwohl et al., 1997; Damon et al., 1998) which
Accession numbers
might explain the absence of inflammation noted
within MCV lesions. Like macrophage inflammatory
protein1(cid:11)(MIP-1(cid:11)),MCCH(type1or2)caninhibit MCV type 1: U60315
colony formation of myeloid, erythroid, and multi- MCV type 2: U96749
potentialprogenitor(hematopoietic)cells(Krathwohl GenPept:
et al., 1997). MCV type 1: g1492091
MCV type 2: g2459795
GENE AND GENE REGULATION
Sequence
Accession numbers
See Figure 1.
MCV MCCH type 1: U60315
MCV MCCH type 2: U96749
Description of protein
Chromosome location
The MCCH protein is 104 amino acids, some 12
amino acids longer than its closest relative, human
For MCV type 1, the M148R ORF is located
MIP-1(cid:11), a CC chemokine (Schall et al., 1990; Miller
approximately 167kb from the left end of the 186kb
and Krangel, 1992). MCCH contains the canonical
genomewithintheBamH1C1fragment.Transcription
cysteine residues, typical of CC chemokines
is towards the right end of the genome.
(Ben-Baruch et al., 1995), which are found at amino
acids 30, 31, 59, and 75 (Figure 2). In addition, and
Regulatory sites and corresponding atypical of other known CC chemokines, the
molluscum protein has two additional cysteine
transcription factors
residues at positions 94 and 101. These motifs have
been found to be conserved in 29 separate MCCH
MCV cannot be grown or studied in cell culture. gene isolates derived from type I and type II MCV
However, cloning of the MC184R ORF into vaccinia (Bugertetal.,1998).Basedoncloningandexpression
Figure1 TheaminoacidsequenceofMCCHfromMCVtype1(bottom)andMCVtype
2 MCV (top).
CC Chemokine of Molluscum Contagiosum Virus 1287
Figure 2 A ‘GAP’ alignment of MIP-1(cid:11) (top) and MCCH-1 (bottom). Both proteins
contain a C-C motif (bold type amino acids at positions 30/31 in MCCH-1), and two
additional conserved cysteines (at positions 59 and 75 in MCCH-1). Both MIP-1(cid:11) and
MCCH-1 also contain an N-terminal secretory signal which is cleaved to generate the
matureprotein.MIP-1(cid:11)iscleavedbetweenaminoacidsS/Aatposition23/24.MCCH-1
iscleavedbetweenresiduesS/Latposition24/25.Theproteoglycan-bindingsiteissetin
bold type in MIP-1(cid:11) and just precedes the conserved cysteine at position 75.
of the MCCH type 1 protein in vaccinia, there is a RECEPTOR UTILIZATION
functional N-terminal 24 amino acid secretory signal
which is cleaved releasing the mature MCCH protein
MCCH can utilize a variety of CC and CXC
from the infected cell (Bugert et al., 1998).
chemokinereceptors.Interactionhasbeenspecifically
The receptor site of CC chemokines consists of an
demonstrated with CCR1 and/or CCR5, CCR2,
N-terminal10aminoaciddomainlocatedadjacentto
CCR8, CXCR1, and/or CXCR2 and CXCR4
cleaved secretory signal peptide. One key feature of
(Damon et al., 1998).
MCCH is deletion or absence of fourcritical residues
withinthisdomain.Thesemissingaminoacidsleadto
aproteintruncatedattheN-terminusfollowingsignal
peptidecleavage.Thesemissingaminoacidscomprise IN VIVO BIOLOGICAL
that portion of the receptor binding site which
ACTIVITIES OF LIGANDS IN
activates the engaged receptor (Clark-Lewis et al.,
1995). It has been proposed that MCCH might bind ANIMAL MODELS
but fail to activate the receptor, thereby acting as a
chemokine antagonist (Senkevich et al., 1996). A Normal physiological roles
secondpossibilityfornonproductivesignalmediation
may reside within a proteoglycan-binding site found
The proposed role of MCCH is the prevention of
within both MCCH and CC chemokines. In the case
inflammation within MCV lesions.
of MIP-1(cid:11), this motif consists of the sequence
‘KRSTQV’. Mutagenesis experiments have shown
that introducing neutral or acidic amino acids into
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