Research Paper |
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Acta Biochim Biophys Sin |
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doi:10.1111/j.1745-7270.2005.00097.x |
Cloning, Structural
Organization and Chromosomal Mapping of Rat Costimulatory Molecule 4-1BBL
Qiu-Ming DONG1, Li-Jie MA2, Guang-Bo ZHANG1, Ya-Fang WU3, Jia-Yao SHEN1, Ying CHEN1, Yong-Jing CHEN1, Xiang-Ke PU1, Sai-Yu HANG1, and Xue-Guang ZHANG1*
1 Biotechnology
Institute, Soochow University, Suzhou 215007, China;
2 Genetics
Institute, Fudan University, Shanghai 200433,
China;
3 First Affiliated Hospital
of Soochow University, Suzhou 215006, China
Received: April 22,
2005
Accepted: July 18,
2005
*Corresponding
author: Tel, 86-512-65104909; Fax, 86-512-65104908; E-mail,
[email protected]
Abstract 4-1BBL (TNFSF9) is
a member of the tumor necrosis factor (TNF) ligand superfamily, which is
expressed on some activated antigen presenting cells and B cells. We isolated a
rat cDNA clone encoding the rat homologue of the human 4-1BBL (GenBank
accession No. AY259541). The deduced rat 4-1BBL protein, consisting of 308
amino acids with a molecular weight of 33,469 Da, was a typical type II transmembrane
glycoprotein, the same as human and murine 4-1BBL. “SDAA” in the
cytoplasmic domain of rat 4-1BBL was deduced to act as the phosphorylation site
for casein kinase I (“SXXS” motif), which is present in the
cytoplasmic domains of human and murine 4-1BBL, and all other TNF ligand family
members known to utilize reverse signaling. The two introns of 4-1BBL were also
cloned (GenBank accession No. AY332409). Rat 4-1BBL is much more homologous
with murine 4-1BBL than with human 4-1BBL, in both nucleotide and amino acid
sequences. Rat 4-1BBL was expressed in all tested tissues: brain, lung, colon,
liver, thymus, testicle, kidney, adrenal, stomach, spleen and heart. The
chromosomal location of rat 4-1BBL was first identified by
bioinformatics, then by fluorescence in situ hybridization at 9q11
(GenBank accession UniGene No. Rn.46783). Rat, murine and human 4-1BBL
genes are evolved from a common gene. The identification and characterization
of the rat counterpart of human 4-1BBL will facilitate studies of the
biological function of this molecule.
Key words TNF superfamily; rat;
4-1BBL; cloning; mapping
Over the past several years, costimulatory molecules belonging to
the tumor necrosis factor (TNF) receptor and TNF ligand superfamilies have been
identified and characterized [1,2]. These include CD27/CD27L, CD30/CD30L
(CD153), CD40/CD40L (CD154), OX40 (CD134)/OX40L and 4-1BB (CD137)/4-1BBL. These
molecules are type II transmembrane glycoproteins, except for LT-a which is the
only entirely secreted tumor necrosis factor-like protein. The members of the
TNF ligand superfamily share common biological activities, but some properties
are shared by only some ligands, while others are unique. The diverse
biological activities triggered through tumor necrosis factor receptor (TNFR)
are mainly related to the regulation of cellular activation, including immune responses
and inflammatory reactions, as well as the pathology of a series of human
diseases.
The murine 4-1BBL cDNA was isolated from a murine thymoma cell line
in 1993 using an expression screening approach [3]. In 1994, Alderson et al.
[4] utilized cross-species hybridization to isolate a cDNA encoding human
4-1BB (hu4-1BB). A fusion protein of the extracellular portion of hu4-1BB
coupled to the Fc region of human IgG1 (hu4-1BBL.Fc) was then used to identify
and clone the gene for human 4-1BBL from an activated CD4+ T
cell clone using a direct expression cloning strategy. Human and murine 4-1BBL
genes are located on human chromosome 19p13 and mouse chromosome 17D,
respectively. Human 4-1BBL is expressed primarily on professional antigen presenting
cells (APCs), such as mature dendritic cells, activated B cells and activated macrophages
[5,6], and is also expressed inducibly in T lymphocytes [7] and constitutively
in monocytes [4]. 4-1BB is expressed on CD4 and CD8 T cell lines [8]. Agonistic
antibodies and the ligand of 4-1BB enhance lymphocyte activation [6,7,9–11], and the
4-1BB protein has an opposite effect in that it inhibits proliferation of
activated T lymphocytes and induces programmed cell death [3,6,7,9,10]. This
means that a reverse signal is transmissive through the ligand [12].
In exploring the physiological and pathological functions of
4-1BBL, the rat system has some advantages over the human and murine systems.
Superior models of autoimmune diseases, such as collagen-induced arthritis,
experimental autoimmune uveoretinitis and experimental allergic
encephalomyelitis, have been developed [13,14]. Some models of human diseases,
such as the human T-cell lymphotropic virus-1-associated pathologies [15], have
only been set up in the rat system.
In order to facilitate the study of 4-1BBL, we cloned rat 4-1BBL
using Internet resources and characterized its expression and chromosome
mapping in the rat system.
Materials and Methods
Animal and cDNA library
Six-week-old male Sprague-Dawley (SD) rats (Rattus norvegicus)
were purchased from Shanghai Institutes for Biological Sciences (Shanghai,
China). cDNA library of rat fetal brain was kindly provided by Dr. Long Yu (Fudan University, Shanghai, China).
Rat 4-1BBL cDNA cloning and
sequence analysis
Murine 4-1BBL mRNA was used to blast
rat expressed sequence tags (ESTs) in GenBank (http://www.ncbi.nlm.nih.gov/blastn).
Primers were designed by comparing murine 4-1BBL mRNA and rat ESTs. Polymerase
chain reaction (PCR) was performed using a cDNA library of rat fetal brain and
PCR product was purified using a PCR product purification kit (Promega,
Madison, USA), then ligated to the pMD18-T vector (TaKaRa, Japan). The cDNA
insert was sequenced on both strands using synthetic oligonucleotide primers
and dye-labeled terminator/Taq DNA polymerase on automated fluorescent
DNA sequence (Sangon, Shanghai, China). Alignment of amino acid sequences and
estimation of homology were performed using DNAtool 6.0.122 (http://www.crc.dk/dnatools) and
ClustalW (http://www.ebi.ac.uk/clustalw)
softwares.
Intron cloning
Rat genome DNA was extracted from adult rat brain using
phenol-chloroform. Primers were designed by comparing rat 4-1BBL cDNA
with the murine 4-1BBL genome. PCR products were ligated to the pMD18-T
vector and were sequenced.
Expression of rat 4-1BBL
Total RNA was extracted from 11 rat tissues using Trizol
(Invitrogen, Carlsbad, USA) and cDNA synthesis was performed using RevertAid
M-MuLV reverse transcriptase (Fermentas, Lithuania). Reverse transcription
(RT)-PCR was performed with rat 4-1BBL cDNA primers and rat b-actin primers
to quantify the relative abundance of 4-1BBL mRNA in each tissue. Primers of
rat b-actin are as follows: 5‘-TAAAGACCTCTATGCCAACAC-3‘, 5‘-TAAAGCCATGCCAAATGTCTC-3‘.
Chromosome mapping by UniGene
Human chromosome 19 and murine chromosome 17 were used to blast the rat genome in GenBank, then
UniGenes were analyzed (http://www.ncbi.nlm.nih.gov/blast/unigene).
Fluorescence in situ hybridization
Rat G-band metaphase chromosomes were prepared using marrow from an
SD rat by cell cycle synchronization [16]. G-banded metaphases were located
and photographed. Giemsa stain was removed with ethanol and the slides were
treated with DNase-free RNase (100 mg/ml) at 37 ºC for 1 h in 2´SSC. Before
hybridization the chromosomes were dehydrated through an ethanol series (70%,
95%, 100%). The 2.0 kb 4-1BBL genomic DNA fragment was generated with cDNA
primers and subcloned into pMD18-T vector. DNA probes were labeled with biotin-14-dATP
(Gibco BRL, Carlsbad, USA) by nick-translation, then the unincorporated
nucleotides were removed by ethanol precipitation in the presence of 20 mg glycogen and
stored at –20 ºC. In situ hybridization and detection were performed as
described previously [17] with a slight modification. In brief, 50–100 ng of
biotinylated probe was applied to each slide under sealed glass coverslips.
Hybridization buffer contained 1.5 ml probe (50–100 ng), 1.5 ml 100 mg/ml denatured
salmon sperm DNA (100 mg/ml) (Sigma, St. Louis, USA), and 12 ml hybridization solution
VII (Oncor, Gaithersburg, USA). The chromosome DNA was denatured in 70%
formamide in 2´SSC for 3 min, and probe was denatured at 72 ºC for 10 min. Hybridization
was performed in a humidified box at 42 ºC for approximately 16 h. Subsequently
the slides were washed in 2´SSC at 72 ºC for 5 min, in 1´PBD for 2 min and in 100 ml blocking
solution at 37 ºC for 10 min. The biotin-labeled probe DNA was visualized and
amplified by the fluorescein-isothiocyanate (FITC)-conjugated avidin and
biotinylated anti-avidin system (biotin-FITC detection kit; Oncor). Individual
chromosomes were identified by counterstaining with
4,6-diamidino-2-phenylindoledihydrochloride (DAPI; Sigma). Separated images of
DAPI-banded chromosomes were obtained and merged electronically using
microscope Leica Q550 CW (Leica, Wetzlar, Germany) and image analysis software
Leica QFISH V2.1 (Leica).
Results
Cloning of rat 4-1BBL cDNA
In order to identify rat 4-1BBL, murine 4-1BBL mRNA was used to blast the rat ESTs in GenBank. Two
highly homologous rat ESTs were obtained (GenBank accession No. BF565084 and
BF394106) and coincidently the two ESTs properly spanned the murine 4-1BBL
coding region. Primers possibly spanning the possible coding region were
designed according to the two ESTs. Electrophoresis of the PCR product on 1%
agarose gel showed a 1000-bp band as expected. The sequencing result was then
linked with the two ESTs, and a 1328-bp fragment of rat 4-1BBL cDNA was
obtained. The sequence of the cDNA clone shown in Fig.
1(A) contained a single large open reading frame (ORF) encoding a protein
of 308 amino acid residues. Hydrophilicity analysis predicted a single
hydrophobic domain encompassing AA83 to AA102 and no signal sequence. Thus,
like murine and human 4-1BBL, this protein was predicted to be a type II
membrane protein with its carboxy-terminal domain extracellular. Like murine
4-1BBL (containing three potential N-linked glycosylation sites: AA139, AA161,
AA293), the extracellular domain of rat 4-1BBL also contains three potential
N-linked glycosylation sites: AA138, AA160 and AA292, while human 4-1BBL does
not. The nucleotides of the possible coding region of rat 4-1BBL has 88% and
37% homology with that of murine and human 4-1BBL, respectively, in which the
cytoplasmic domain is 85%, 30%; the transmembrane domain is 81%, 33% and the
extracellular domain is 89%, 46% homology with murine and human 4-1BBL,
respectively. Alignment of the predicted protein product of this rat cDNA with
that of murine 4-1BBL and human 4-1BBL is shown in Fig. 1(B). Rat 4-1BBL
is more closely related to murine 4-1BBL with 83% homology and to a lesser
extent to human 4-1BBL with 31% homology, in which the cytoplasmic domain is
76%, 32%, the transmembrane domain is 45%, 40% and the extracellular domain is
87%, 28% homology with murine and human 4-1BBL, respectively. The molecular
weight of the deduced rat 4-1BBL protein is 33,469 Da, and its isoelectric
point is 5.82.
Cloning of rat 4-1BBL
introns
Comparing the rat 4-1BBL cDNA and the murine 4-1BBL genomic
gene, the rat 4-1BBL gene was deduced to have two introns just the same
as murine 4-1BBL. Sequencing results displayed two sequences of 335 bp
and 687 bp, respectively, corresponding to murine intron 1 (389 bp) and intron
2 (754 bp), whereas those of human are 1489 bp and 1783 bp, respectively. Two
rat 4-1BBL introns followed the gt-ag rule (Fig. 2). To test the
accuracy of the results, PCR was performed with the primers which were used in
cloning rat 4-1BBL cDNA and with rat genome DNA as the model. PCR results
showed a band of about 2000 bp as expected (389+754+1000=2043). The intron
nucleotide sequences showed 86% and 85% identity in intron 1 and intron 2,
respectively, between rat and murine 4-1BBL; and 8% (intron 1) and 26% (intron
2) between rat and human. The identity from start codon to stop codon was 86%
between rat 4-1BBL (1946 bp) and murine 4-1BBL (2073 bp), and 13%
between rat 4-1BBL and human 4-1BBL (4027 bp). So rat 4-1BBL
is more homologous with murine 4-1BBL than with human 4-1BBL, in
both nucleotide and amino acid sequences. Human 4-1BBL protein is poorly
homologous with rat 4-1BBL protein and murine 4-1BBL protein (both 31%). Their
genes are all composed of three exons and two introns, in which the lengths of
exon 2 are short: 31 bp (human), 37 bp (rat and murine); and the lengths of
exon 3 are similar: 461 bp (rat), 464 bp (human and murine). The exon 2 is 50%–60% idential among
the three genes, the same as exon 3. Exon 2 and exon 3 mainly encode the
transmembrane and the extracellular domains. Compared with the identities of
nucleotide sequences of the cytoplasmic domain of the three molecules, which
is encoded by exon 1 (34% between human and murine, 22% between human and rat),
the identities of nucleotide sequences of
transmembrane and extracellular domains are higher.
mRNA expression of rat 4-1BBL
RT-PCR results showed that 4-1BBL mRNA was widely but differently
expressed in tested tissues (Fig. 3). The 4-1BBL mRNA level in each
tissue, compared with that of rat b-actin mRNA, was analyzed using bandleader 3.0 (http://www.bio-soft.net/draw.html);
and the relative abundance from high level to low level was as follows: brain,
colon, lung, thymus, adrenal, liver, testicle, kidney, stomach, spleen and
heart.
Rat 4-1BBL chromosomal
mapping by bioinformatics
Chromosome blast
results demonstrated that human chromosome 19 matched rat chromosomes 1, 5, 7,
9, 12 and 16, and murine chromosome 17 matched rat chromosomes 1, 6, 9, 10
and 20 (Fig. 4). Rat 4-1BBL gene was inferred on
chromosome 1 or 9. UniGenes on human chromosome 19, murine chromosome 17, and
rat chromosome 1, 9 were analyzed. We found that the UniGene of human 4-1BBL
locating on human Chr.19:38.82cR is Hs.1524, and the UniGene of murine 4-1BBL
locating on murine Chr.17:799.15cR is Mm.41171. Coincidently another UniGene
(Mm.23982) was also found on murine Chr.17:799.15cR, and this UniGene corresponded
to rat UniGene Rn.14560. Rat UniGene Rn.14560 was the location of rat gene
crumbs 3 (CRB3), which is on rat chromosome 9q11cM (Chr.09:0cR) (http://www.ncbi.nlm.nih.gov/UniGene/clust.cgi?ORG=Rn&CID=14560).
The chromosome locations of human CRB3 and murine CRB3 were
searched on the National Center for Biotechnology Information (NCBI) website,
and it was found that CRB3 was located on human 19p13.3cM (GenBank
accession No. NM_174881, UniGene No. Hs.150319) and murine 17D (GenBank
accession No. NM_177638, UniGene No. Mm.260076), respectively, just the same as
4-1BBL. According to the gene linkage rule, rat 4-1BBL may be on
rat 9q11cM, just like rat CRB3. To prove the deduction, the chromosome
arrangement of genes CRB3, 4-1BBL, C3 and another gene (in
murine called Vav, in human and rat called Vav1) were analyzed,
which are all located on rat chromosome 9q11, human chromosome 19p13.3, and
murine chromosome 17. On human chromosome 19, the nucleotide span number of
the four genes are: CRB3, 6414788-6418232 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=
Graphics&list_uids=92359); 4-1BBL, 6482037-6486933 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=
8744); C3, 6671660-6628878 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=
Graphics&list_uids=718); Vav1, 6723722-6808371 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=
gene&cmd=Retrieve&dopt=Graphics&list_uids=7409). The order
of their locations is CRB3/4-1BBL/C3/Vav1. Because
the murine genome was not obtained on the internet,
UniGene was used to analyze the locations of the four genes on murine
chromosome 17: Vav, murine Chr.17:803.35cR (UniGene No. Mm.57191) (http://rgd.mcw.edu/tools/vcmap/vcmap.cgi?MapName=Murine+VirtualMap+5.0_HS&Chr=17&FirstMarker=C3&FirstPos=795.08&SecondMarker=1700093E07
Rik&SecondPos=859.3); CRB3, murine Chr.17:799.15cR (UniGene
No. Mm.23982); 4-1BBL, murine Chr.17:799.15cR (UniGene No. Mm.41171); C3,
murine Chr.17:795.08cR (UniGene number Mm.1913). The order of their locations
is C3/CRB3(4-1BBL)/Vav. Fig. 4(C) shows that
the relation of the genes on rat chromosome 9 is Vav1/UniGene
Rn.14560/C3, and UniGene Rn.14560 is CRB3. The three genes are
all on rat 9q11, so rat 4-1BBL is also located on rat 9q11, and its
UniGene accession No. is Rn.46783.
Rat 4-1BBL chromosomal
mapping by fluorescence in situ hybridization
The biotin-labeled probe DNA was prepared with rat genome 4-1BBL
corresponding to the 2.0 kb PCR product. The signal was amplified by
immunofluorescence. Positive signals were visualized on both homologous
chromosomes only on 9q11 in 90% of the chromosome spreads which were
investigated (Fig. 5). This is consistent with the result of
chromosomal mapping by informatics using UniGenes.
Discussion
As other TNFR superfamily members, 4-1BB uses adaptor molecules,
which are called TNFR-associated factors (TRAFs), to transduce a downstream
signal. The cytoplasmic domain of 4-1BB is able to bind specifically with
TRAF1, TRAF2 and TRAF3 [10,18,19]. Accumulating evidence indicates that there
exists a signal transduction pathway by way of the 4-1BB ligand as well as the
4-1BB. Cross-linking of 4-1BBL with insect cells, which express 4-1BB, induces
strong B-cell proliferation synergistically with anti-IgM antibody [5].
Similarly, cross-linking of 4-1BBL by soluble 4-1BB-Fc fusion protein induces
monocyte activation so that the expression of IL-6, IL-8, TNF-a and ICAM is
up-regulated, whereas FcgR III expression is down-regulated [20]. Signals by way of 4-1BBL
also lead to a strong production of macrophage colony-stimulating factor in
monocytes, which in turn functions as a potent survival factor for monocytes
[21]. In addition, the “reverse signaling” through 4-1BBL mediates
monocyte proliferation by an autocrine mechanism which is still unknown yet
[22]. In T lymphocytes, T-cell proliferation induced by anti-CD3 antibody is
inhibited by cross-linking of 4-1BBL [12]. Furthermore, this inhibition of
T-cell proliferation is accompanied by cell apoptosis. The apoptotic signal transmitted
by 4-1BBL is independent of Fas [23]. Therefore 4-1BBL signaling mediates two
opposite biological phenomena, cell survival and apoptosis, depending on cell
type. Even though reverse signaling through TNF ligand family members has been
well documented, its molecular mechanism remains undiscovered. Interestingly, a
phosphorylation site for casein kinase I (SXXS) is present in the cytoplasmic domains
of all TNF ligand superfamily members, which were known to utilize the reverse
signaling, CD30L, 4-1BBL, CD40L and FasL, except OX40 ligand [24]. In
transmembrane TNF-a, this motif has been the phosphorylation target for casein kinase,
and treatment of a macrophage cell line with dimeric soluble TNFR leads to the
dephosphorylation of total cellular transmembrane TNF-a. One biochemical change
following the dephosphorylation is an elevation of intracellular calcium levels
[24]. This motif appears as “SDAA” in the deduced rat 4-1BBL amino
acid sequence, but appears as “SDAS” in human 4-1BBL and as
“SDAA” in murine 4-1BBL. The difference is in that “Ser”
contains -OH while “Ala” contains -H. Ser is a polar amino acid,
while Ala is between polar and non-polar, and they are both uncharged. So rat
“SDAA” possibly acts as the phosphorylation target for casein kinase.
The existence of a phosphorylation site for casein kinase I in the cytoplasmic
domain of the three molecules probably makes them function similarly in
“reverse signal” transmission. Like murine 4-1BBL, rat 4-1BBL also
contains additional 55 N-terminal amino acid residues belonging to the cytoplasmic
domain, which is not found in the human homologue. In co-stimulation signal
transmission, especially in “reverse signal” transmission, it is
unknown what difference was caused by the lack of amino acid residues and
potential N-linked glycosylation sites in human 4-1BBL. Study on rat 4-1BBL
will make its mechanism of function and of reverse signal transmission
understood.
A simple method was used here to compare the cloning of murine and
human 4-1BBL. The completion of the Human Genome Project has made a lot of
data available on gene sequences, location, expression, and function analysis,
which provides a short cut to clone genes with ESTs and homology analysis.
Compared with murine and human 4-1BBL, the rat 4-1BBL was cloned and mapped by in
silicon cloning and chromosome mapping, which is also a short cut. Rat
4-1BBL was firstly identified to locate at 9q11 (GenBank accession UniGene No.
Rn.46783), the same as the CRB3 gene, by bioinformatics and FISH
methods. These two genes also appeared at the same site both in human (19q13)
and murine (17D). The gene structure of rat, murine and human 4-1BBL are
similar. 4-1BBL, CRB3, C3 and Vav1 (Vav) are
all lined at rat chromosome 9, murine chromosome 17 and human chromosome 19.
So rat, murine and human 4-1BBL probably evolved from a common ancestor
gene. The identification and characterization of the rat counterpart of human
4-1BBL will facilitate the study of the biological functions of this molecule.
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