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J Biol Chem, Vol. 274, Issue 17, 11455-11458, April 23, 1999
From the Department of Biochemistry, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575 Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Transport system
xc The transport of amino acids across the plasma membrane of
mammalian cells is performed by specific systems of mediation acting on
discrete groups of substrate molecules (1). We have described in
cultured mammalian cells a Na+-independent anionic amino
acid transport system highly specific for cystine and glutamate (2, 3).
This system, designated as system xc Thus the physiological role of system
xc Expression Cloning--
To isolate a cDNA encoding the
cystine/glutamate transporter, we used an expression cloning approach
similar to that used to clone the glucose transporter (10). Mouse
peritoneal macrophages were collected from female C57BL/6N mice that
had received 4 days previously an intraperitoneal injection of 2 ml of
4% thioglycollate broth. The mRNA fraction was isolated from the
cells cultured for 8 h with 0.1 mM diethyl maleate and
1 ng/ml LPS (DIFCO, Salmonella typhosa 0901), and a
unidirectional cDNA library was constructed using the
SuperScriptTM Plasmid System (Life Technologies, Inc.). For
screening, plasmids from pools of approximately 1000 clones were
isolated using a purification kit (Qiagen), linearized with
NotI, and transcribed in vitro in the presence of
5' 7MeGpppG 5'. Xenopus laevis oocytes were manually
defolliculated and injected with 2.5-50 ng of the transcribed cRNA in
50 nl water/oocyte. Two days after injection, the rate of uptake of
cystine by 3-5 oocytes was measured at 30 °C for 10 min in 125 µl
of uptake medium. The uptake medium contained [14C]cystine in modified Barth's saline (10 mM HEPES, pH 7.5, 88 mM NaCl, 1 mM
KCl, 0.3 mM Ca(NO3)2, 0.4 mM CaCl2, 0.8 mM MgSO4, 50 units/ml penicillin, and 50 µg/ml streptomycin). The uptake was
terminated by rapidly rinsing the oocytes three times with ice-cold
modified Barth's saline, and then the radioactivity in oocytes was
counted. The cDNA was sequenced on both strands by dye terminator
cycle sequencing method by PE Applied Biosystems.
Functional Characterization by Xenopus Oocyte
Expression--
Oocytes were injected with 2.5 ng each of the cloned
cRNA. Two days after injection, the rates of uptake of various
14C-labeled amino acids were measured as described above.
For Na+-free uptake, NaCl was replaced by choline chloride.
For efflux experiments, five oocytes were incubated in 125 µl of
modified Barth's saline for 10 min at 30 °C in the presence or
absence of 0.1 mM L-cystine. Then the saline
was removed and analyzed by a JEOL JLC 300 amino acid analyzer.
Northern Blot Analysis--
The cDNA probes for clones Dr4
and Cm30 were PstI restriction fragments from 365 up to 1211 base pairs and from 102 up to 947, respectively. Both probes were
labeled using [ In Vitro Translation--
In vitro translation of
cRNA was performed using the rabbit reticulocyte lysate system with or
without canine pancreatic membrane (Promega). The experiments were done
according to the manufacturer's protocol.
To clone system xc
found in plasma membrane of
cultured mammalian cells is an exchange agency for anionic amino acids
with high specificity for anionic form of cystine and glutamate. We have isolated cDNA encoding the transporter for system
xc from mouse activated macrophages
by expression in Xenopus oocytes. The expression of system
xc activity in oocytes required two
cDNA transcripts, and the sequence analysis revealed that one is
identical with the heavy chain of 4F2 cell surface antigen (4F2hc) and
the other is a novel protein of 502 amino acids with 12 putative
transmembrane domains. The latter protein, named xCT, showed a
significant homology with those recently reported to mediate cationic
or zwitterionic amino acid transport when co-expressed with 4F2hc. Thus
xCT is a new member of a family of amino acid transporters that form
heteromultimeric complex with 4F2hc, with a striking difference in
substrate specificity. The expression of system
xc was highly regulated, and
Northern blot analysis demonstrated that the expression of both 4F2hc
and xCT was enhanced in macrophages stimulated by lipopolysaccharide or
an electrophilic agent. However, the expression of xCT was more
directly correlated with the system xc activity.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
(4), is an exchange agency, and the anionic form of cystine is
transported in exchange for glutamate (5). The exchange is obligatory
with a molar ratio of 1:1. System xc
is almost ubiquitous in cultured mammalian cell lines (6), and the
physiologic flows via this system are the entry of cystine and the exit
of glutamate because cystine is very rare in cytosol due to a rapid
reduction to cysteine, whereas the concentration of glutamate is much
higher in cells than in extracellular fluid (5). Cystine taken up by
the cell via system xc is rapidly
reduced to cysteine, which is incorporated into proteins and
glutathione. Because cysteine is a rate-limiting precursor for
glutathione synthesis, the intracellular level of glutathione is
regulated by the system xc activity
(1, 7). The expression of system xc in
cultured cells seems to be highly regulated. Its activity is induced by
electrophilic agents, depletion of cystine, or by oxygen (8), and this
induction may be interpreted as an adaptive response because these tend
to decrease glutathione. In macrophages lipopolysaccharide
(LPS)1 is a potent inducer of
the system xc activity and increases
glutathione (9), which may serve to protect the cells against the
oxidative stress at the sites where they are activated.
in cultured cells is obvious.
However, the molecular nature of the transporter remains totally
unknown. In this communication a cDNA library has been constructed
from mouse peritoneal macrophages in which the system xc activity is induced and cloning and
expression of cDNA encoding the transporter protein(s) for system
xc have been performed.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
-32P]dCTP and RediprimeTM
II random prime labeling system (Amersham Pharmacia Biotech). RNA was
electrophoresed on a 1% agarose gel in the presence of 2.2 M formaldehyde, transferred to Hybond N+
membrane (Amersham Pharmacia Biotech), and hybridized in a solution containing 50% formamide for 16 h at 42 °C. The membranes were washed twice for 15 min at room temperature with 1 × SSC, 0.1% SDS and then washed twice for 15 min at 68 °C with 0.25 or 0.1 × SSC, 0.1% SDS.
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
transporter,
cRNA was prepared from pools of about 1000 clones and tested using the
expression of cystine uptake activity in Xenopus oocytes.
One of the pools was positive, and it was divided into 11 groups (A
through K), which were tested subsequently. However, none of these
groups were positive. Because the mixture of cRNAs prepared from these
11 groups was positive, we hypothesized that the transporter is
composed of heteromultimeric complex. Thus the mixture of cRNAs from 10 groups, i.e. cRNAs from those lacking one specified group
(
A through K) was tested, and the results showed that C and D
were negative, whereas the other nine were positive (Fig.
1). This indicates that both cRNAs from
group C and those from group D are required for the expression of the
cystine transport activity. Then we found that the combination of cRNAs
from group C and those from group D were sufficient for the expression.
Group C was further subdivided and tested in the presence of total
cRNAs from group D until a single clone, Cm30, was isolated. Similarly
the group D was subdivided and tested in the presence of cRNA from
Cm30, and a single clone Dr4 was isolated. Sequence analysis of the
insert of Cm30 proved its identity with the cDNA of 4F2 heavy chain
(4F2hc) cell surface antigen (two nucleotides of 1828 were different
with no change in amino acid sequence). Clone Dr4 insert was composed
of 2250 base pairs and contained a single open reading frame that
encodes a putative protein designated xCT (system
xctransporter-related protein).
View larger version (21K):
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Fig. 1.
The rate of uptake of cystine in
Xenopus oocytes injected with cRNA from the plasmids
of various groups divided from the positive pool. The pool of
about 1000 clones that showed the positive signal with respect to
cystine uptake was divided into the 11 groups (A through K), and 10 of
the 11 groups, i.e. lacking one specified group, were put
together, making combinations of all groups except for A ( A), all
groups except for B (B), and so on. cRNAs were prepared from these
combined groups (labeled by A through K) or
from the undivided pool (labeled by All). The cRNA was also
prepared from the mixture of groups C and D (C+D). They were
injected at 50 ng/oocyte, and 2 days after injection, the rates of
uptake of L-[14C]cystine at 50 µM were
measured for 10 min at 30 °C. Data represent the means ± S.D.
of three independent experiments.
cRNAs of 4F2hc and xCT were about 2 kb, and when they were injected
into Xenopus oocytes in equal amounts, the uptake of cystine and glutamate was increased greatly and the uptake of aspartate was
increased to a much lesser extent (Fig.
2). The uptake of arginine, leucine,
serine, and alanine remained unchanged or slightly increased. cRNA of
4F2hc or xCT alone did not enhance the uptake of cystine and glutamate
at all. However, 4F2hc cRNA significantly enhanced the uptake of
arginine and leucine, probably because 4F2hc induces system
y+L-like activity in oocytes (11, 12). The uptake of
cystine and glutamate co-expressed by 4F2hc and xCT was mainly (83 ± 5%) Na+-independent, with Km of
0.081 mM for cystine and 0.16 mM for glutamate.
To determine the specificity of this uptake, the ability of various
amino acids to inhibit the uptake of cystine or glutamate was
investigated. The cystine or glutamate uptake exhibited very similar
inhibitor specificity to each other, and the uptake of cystine was
potently inhibited by glutamate and vice versa (Fig.
3). System
xc mediates an obligatory exchange
with 1:1 stoichiometry. Because the free glutamate pool in
Xenopus oocytes is very large, whereas cystine/cysteine
content is trivial (13), we measured the influx (uptake) of cystine and
the efflux of glutamate simultaneously by using
[14C]cystine for the influx measurement and by the direct
determination of glutamate effluxed from the oocytes into the medium by
amino acid analyzer. Results are summarized in Table
I. The efflux of glutamate was dependent
on the presence of cystine in the medium, and its rate was nearly equal
to that of cystine influx, indicating that cystine/glutamate exchange
occurred at a 1:1 molar ratio. Analysis of amino acids in the saline in
which oocytes were incubated showed that the efflux of amino acids
other than glutamate was trivial regardless of the presence of cystine.
All these properties of the cystine/glutamate transport elicited in
oocytes by the co-expression of 4F2hc and xCT are consistent with those
of system xc in mouse peritoneal
macrophages and human fibroblasts (2, 5, 14).
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cDNA for xCT encoded a putative protein of 502 amino acids and a
relative molecular mass of 55.5 kDa (Fig.
4A). Assignment of the first
ATG as the translation initiation site is based on its resemblance to a
consensus sequence (GCCATGG). In vitro translation showed a
band of an approximately 40-kDa protein, which was not glycosylated by
canine pancreatic microsomes (data not shown). Comparison of the
sequence of this predicted protein (xCT) against protein data bases
revealed that the protein is novel and has a significant homology
(44-47% identity) with the recently identified system L-like amino
acid transporters from human (15) and rat (16) and system
y+L-like amino acid transporters from human (17). All of
these proteins induce transport activity only when co-expressed with 4F2hc. Analysis of the amino acid sequence according to the algorithm of Kyte and Doolittle (18) predicts an extremely hydrophobic protein
(Fig. 4B) that may contain as many as 12 membrane-spanning domains.
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Northern blot analysis showed three xCT transcripts (12, 3.5, and 2.5 kb) in macrophages cultured for 8 h with LPS and/or diethyl
maleate (Fig. 5A). These
multiple bands remained after high stringency washing and may represent
alternative splicing, alternative polyadenylation sites, or a
combination of both. xCT-specific signals are not visible in RNA from
freshly prepared macrophages and are very faint in RNA from macrophages
cultured for 8 h. The pattern of expression of xCT transcript is
consistent with the system xc
transport activity of the macrophages previously reported (9). Fig.
5B shows that 4F2hc message was expressed at a very low
level in freshly prepared macrophages and at a much higher level in macrophages cultured for 8 h with or without LPS and diethyl
maleate. Expression of xCT in major organs was investigated (Fig.
5D), and the 12-kb message was expressed in brain but not in
other organs tested.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Recently evidence has been presented to indicate a heterodimeric
protein structure of some amino acid transporters in mammals (15-17).
The common component is 4F2hc, which has been implicated in system
L-like and system y+L-like transport activity. The
counterpart component has been cloned on the assumption that the
transport activity is induced when it is co-expressed with 4F2hc. Cell
surface glycoprotein 4F2hc is less hydrophobic and contains a single
transmembrane domain, whereas the counterpart proteins are much more
hydrophobic with 12 predicted transmembrane domains. Experiments using
sulfhydryl-blocking agents or cysteine-to-serine mutagenesis in 4F2hc
suggested that the heterodimeric complex is linked by a disulfide
bridge involving Cys109 of 4F2hc (17, 19). System
xc is an anionic amino acid transport
system, and the present study clearly indicated that the transporter
for system xc belongs to the group
requiring 4F2hc as an essential component (provisionally designated as
4F2 group). In xCT the conserved cysteine residue, which is a putative
site for a disulfide bond with Cys109 of 4F2hc, was located
at position 158 (Fig. 4A). Thus the membrane topology of
(4F2hc + xCT) transporter is probably very similar to other 4F2 group
transporters, although the substrate specificity is markedly different.
The present study, together with those on 4F2 group transporters,
suggests that one of the most intrinsic features of the 4F2 group
transporters is an exchange of the substrate amino acids. System L- and
y+L-like transport activity expressed in oocytes seem to
show an obligatory exchange, although the molar ratio of exchange is
not determined (15, 16, 20). System L and y+L naturally
expressed in cells show marked transstimulation (1, 21), that is, the
substrate amino acids in one side of the membrane stimulate the exodus
of the substrate amino acids from the opposite side of the membrane.
However, it has not been proved yet that the naturally occurring system
L or y+L is locked into exchange, and the possibility that
the obligatory exchange mechanism of an L- or y+L-like
system is an oocyte artifact has not been ruled out. In contrast the
transport by system xc naturally
occurring in cells such as fibroblasts has been established to be an
obligatory exchange with a molar ratio of 1:1, consistent with the
transport expressed by (4F2hc + xCT) in oocytes. Although further study
is required, it is likely that the Na+ independence and
obligatory exchange are characteristics of 4F2 group transporters.
Although the significance of system xc
is evident in cultured cells, little is known about the physiological
relevance of system xc in
vivo. System xc might affect
plasma cystine/cysteine level as predicted from the cell culture model
(7). The plasma cystine level is suggested to be a physiological
regulator of immune responses (22), particularly in HIV infection where
glutathione plays an important role in HIV suppression and T cell
function (23). Isolation of cDNA clone for system
xc will enable us to investigate a
physiological role of this system xc
transporter in vivo.
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ACKNOWLEDGEMENTS |
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We thank Drs. K. Sakamoto and H. Kitayama for helpful discussions.
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FOOTNOTES |
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* This work was supported in part by grants from the Tokyo Biochemical Research Foundation and the Ministry of Education, Science, and Culture in Japan.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AB022345.
To whom correspondence should be addressed. Tel.: 81-298-53-3066;
Fax: 81-298-53-3039.
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ABBREVIATIONS |
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The abbreviations used are: LPS, lipopolysaccharide; 4F2hc, 4F2 heavy chain; kb, kilobase(s); HIV, human immunodeficiency virus.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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E. Gasol, M. Jimenez-Vidal, J. Chillaron, A. Zorzano, and M. Palacin Membrane Topology of System Xc- Light Subunit Reveals a Re-entrant Loop with Substrate-restricted Accessibility J. Biol. Chem., July 23, 2004; 279(30): 31228 - 31236. [Abstract] [Full Text] [PDF]
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-actin (C). D,
poly(A)+ RNA was purified from mouse heart (lane
1), lung (lane 2), liver (lane 3), kidney
(lane 4), and brain (lane 5), and 4 µg of each
was loaded. The hybridization was performed with
32P-labeled cDNA of xCT.