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First published online August 3, 2006
Journal of Experimental Biology 209, 3071-3078 (2006)
Published by The Company of Biologists 2006
doi: 10.1242/jeb.02349
Identification of two cationic amino acid transporters required for nutritional signaling during mosquito reproduction
Center for Disease-Vector Research, Department of Entomology and the Institute for Integrative Genome Biology, University of California Riverside, 3401 Watkins Drive, Riverside, CA-92521, USA
Author for correspondence (e-mail:
alexander.raikhel{at}ucr.edu)
Accepted 26 May 2006
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Summary |
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Key words: TOR, vitellogenesis, slif, iCAT2, Aedes aegypti, fat body
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Introduction |
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). Significant physiological differences are documented
between autogenous and anautogenous mosquitoes. Typically, autogenous
mosquitoes emerge from the pupal stage with larger stores of nutrients and
higher titers of hemolymph amino acids (AAs)
(Su and Mulla, 1997a;
Su and Mulla, 1997b).
Egg development in female mosquitoes begins with vitellogenesis, the tissue
specific expression, synthesis and secretion of yolk protein precursors (YPPs)
by the fat body. The secreted proteins are then transported to the ovaries
where they are incorporated into the developing oocytes
(Raikhel et al., 2002;
Raikhel and Dhadialla,
1992).
In Aedes aegypti (the anautogenous species used in this work),
after pupation and a 3-day preparation period, the mosquito enters a
previtellogenic state of arrest during which yolk protein precursor (YPP) gene
transcription is repressed until stimulation by a blood meal
(Attardo et al., 2003;
Martin et al., 2001a). After
blood feeding, transcription of YPP genes is upregulated in the fat body.
Expression of the major YPP gene, vitellogenin (vg) peaks at
around 24 h and subsides between 36 and 48 h after a blood meal (PBM).
vg is both directly and indirectly regulated by the steroid hormone
20-hydroxyecdysone (20E), the titers of which positively correlate with
vg expression during vitellogenesis
(Deitsch et al., 1995;
Kokoza et al., 2001;
Martin et al., 2001b). 20E
acts as the primary signal regulating vg expression. However, 20E
activation of vg appears to be conditional. Exogenous treatment of
competent mosquitoes with physiological levels of 20E does not result in
activation of vitellogenesis (Lea,
1982).
Studies concerning the effects of AA levels upon egg development in
mosquitoes have shown that a number of AAs are essential for oogenesis
(Lea et al., 1956;
Uchida, 1998;
Uchida et al., 2001). Analysis
of the dynamics of hemolymph AA concentrations shows significant increases in
total AA concentration within 8 h post blood meal. The increased AA
concentrations last until 3 days post blood meal
(Uchida et al., 1990). Our
recent work has demonstrated that AAs act directly upon the fat body to
activate basal expression of the vg gene and that without them 20E is
incapable of activating vg
(Hansen et al., 2004).
Furthermore, we discovered that the nutritionally regulated TOR (target of
rapamycin) kinase signal transduction pathway mediates the AA signal. The TOR
kinase is a serine/threonine kinase, which is ubiquitously expressed in
eukaryotes (Raught et al.,
2001). It has been well characterized in its role as a nutrient
sensor in multiple systems including Saccharomyces cerevisiae, Drosophila
melanogaster and vertebrate cells
(Colombani et al., 2003;
Cooper, 2002;
Lynch et al., 2000).
In the D. melanogaster fat body, TOR-mediated AA signaling
regulates the growth rate of the whole organism. This system was identified
during a search for growth phenotypes by a transposon-mediated mutagenesis
study. The disrupted gene was found to be a cationic AA transporter (CAT)
called slimfast (slif). Disruption of slif in the
fat body resulted in global inhibition of growth as well as a sensitivity to
arginine starvation. The phenotypic effects of slif knockdown
resemble those of rapamycin treatment, an inhibitor of the TOR pathway
(Colombani et al., 2003). Two
proton-assisted AA transporters (PAT) that genetically interact with TOR have
been identified in Drosophila
(Goberdhan et al., 2005).
Among them, the gene pathetic (path) encodes a low
capacity/high affinity transporter, which has been suggested to play a role as
an AA sensor in the TOR pathway.
In this work we continue our characterization of AA signaling in mosquito vitellogenesis by analysis of the effect that specific AAs have upon vitellogenesis, and determine which are essential and non-essential for this process. We also expand our analysis to include the involvement of amino acid transport in this system through the cloning and characterization of the A. aegypti homologue of slif and a novel cationic AA transporter iCAT2.
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Materials and methods |
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).
Fat body culture
The fat body tissue culture system was described previously
(Deitsch et al., 1995;
Raikhel et al., 1997). Media
in which AAs were removed was supplemented with an equal molar amount of
mannitol (Sigma-Aldrich Chemicals, St Louis, MO, USA), to compensate for
changes in osmotic pressure. Fat bodies were incubated for 3 h at 27°C
before collection and processing.
Molecular biology techniques and cloning
Standard procedures were used for recombinant DNA manipulations
(Ausubel et al., 1991). DNA
sequences homologous to D. melanogaster slif and iCAT2 were
identified in the An. gambiae genome project database and aligned
using ClustalW
(http://clustalw.genome.ad.jp/).
Highly conserved regions were chosen as a template for primers to amplify
partial cDNAs of the A. aegypti homologues from fat body cDNA.
5'- and 3'-ends of the cDNAs were amplified by rapid amplification
of cDNA ends (RACE) PCR using the Smart cDNA RACE Amplification Kit (BD
Clontech, Palo Alto, CA, USA). All PCR products were cloned in pCRII-TOPO
vector (Invitrogen, Carlsbad, CA, USA). Analysis of primary predicted protein
structure was performed at EXPASY
(http://us.expasy.org/).
Transmembrane domain prediction was created using the TMHMM software at
(http://bioweb.uwlax.edu/Default.htm).
Sequence alignment and phylogenetic analysis
Sequence alignments were performed with ClustalW (default parameters) using
the following amino acid sequences: Aedes aegypti Slimfast (AaSlif)
AAT73699; Anopheles gambiae Slif (AgSlif) EAA09921; Drosophila
pseudoobscura Slif (DpSlif) EAL30882; Drosophila melanogaster
slif (DmSlif) NP_730765; Apis melifera Slif (AmSlif) XP_393144;
Drosophila melanogaster iCAT2 (DmCAT2) AAF49292; Apis
melifera iCAT2 (AmCAT2) XP_393753; Drosophila pseudoobscura
iCAT2 (DpCAT2) EAL29695; Anopheles gambiae iCAT2 (AgCAT2) EAA09874;
Gallus gallus CAT1 (GgCAT1) XP_417116; Rattus norvegicus
CAT1 (RnCAT1) P30823; Homo sapiens CAT1 (HsCAT1) AAH69358; Mus
musculus CAT1(MmCAT1) NP_031539; Rattus norvegicus CAT2 (RnCAT2)
NP_072141; Mus musculus CAT2 (MmCAT2) NP_031540; Homo
sapiens CAT2 (HsCAT2) NP_001008539; Gallus gallus CAT2 (GgCAT2)
XP_420685; Xenopus laevis CAT2 (XlCAT2) AAH78099; Danio
rerio CAT2 (DrCAT2) AAH86843; Mus musculus CAT3 (MmCAT3)
AAH50195; Rattus norvegicus CAT3 (RnCAT3) NP_058913; Homo
sapiens CAT3 (HsCAT3) AAL37184; Tetraodon nigroviridis CAT3
(TnCAT3) CAG11735; Danio rerio CAT3 (DrCAT3) AAH85672.
DAMBE was used to perform phylogenetic analysis of the data set
(Xia and Xie, 2001). A
putative cationic amino acid transporter of Arabidopsis thaliana
(AAN18189) was used as outgroup. Bootstrap values (1000 replicates are
indicated on the nodes of the Bootstrap N-J tree).
Real-time PCR analysis
cDNA synthesis and quantification of specific mRNAs was performed as
previously described (Hansen et al.,
2004). Primers and probes were synthesized by Operon (Operon,
Huntsville, AL, USA): slif sense, CTG GTT GGC TTC GTG AT;
slif antisense, CTC TAG TTG ACT TTC CGA C; slif probe,
(6-FAM) CAT TCG ACA TTC GGT TCT TGG CTC CG (BHQ1-Q); iCAT sense, GGT
ACG CTG ATG GCG TAC ACT G; iCAT antisense, TCC TGA CGC AGG ATA CGT
TGA A; iCAT probe, (AminoC6+TxRed) CCA CAA ACT GCC TCC ATC CC
(BHQ2a-TxRed).
RNA interference
Generation of double-stranded RNAs (dsRNA) was accomplished by cloning
slif and iCAT2 template cDNAs into the pLitmus 28i vector.
dsRNA for the nonfunctional portion of the bacterial gene MAL was utilized as
a negative control. dsRNA was produced by in vitro transcription with
T7-RNA polymerase using the Hiscribe RNAi Transcription Kit (New England
Biolabs, Beverly, MA, USA). Approximately 0.5-1 µg of dsRNA in 0.3-0.5
µl of H2O was injected into the thorax of
CO2-anesthetized 1 day-old female mosquitoes. The mosquitoes were
allowed to recover for 5 days before further processing.
dsRNA was produced to a 774 nucleotide (nt) region of slif, spanning from nt 1192 to nt 1965, a 1137 bp fragment of iCAT2 spaning from nt 1046 to nt 2182, and to a 912 bp fragment of a neutral AA transporter (NAT) spanning from nt 324 to 1235 using the MEGAscript® T7 Kit (Ambion, Austin, TX, USA). The primers used to generate the template cDNAs for dsRNA synthesis were: slif sense, gga gtt tgc cgc ttt cac gat cgg gtg gaa tct; slif antisense, agc gcg ttc gga gat ttg gca atg ttc agg ttg aac; iCAT2 sense, aga tag ctc cca tgg agt ggg act tca tgt cca gc; iCAT2 antisense, gca gca ggc cga gaa ggg tac cgg cca ggg tca ag; NAT sense, gtg cta tgc aga act ggg cac gg; NAT antisense, aac gac tcg acg ata ctg ctg tag gtg a. The effectiveness of the knockdown was tested using RT-PCR: slif sense: atg gac aaa ttc ttc aag gcc ctc tgc cgc aaa aaa cca; slif antisense: cta cgc ctt ttc gag tcc tac cat gca gaa cgg att ctc tag t; iCAT2 sense: atg tcc acc ccc tca tgc tgg aag att ctg acg cga aag aaa att; iCAT2 antisense: cag atg acg tca gtg ccc ata ctt gag ttt ggt cca tcc ggg gcg; NAT sense: ggg aat ttt cat ctc gcc gaa gg; NAT antisense: cac gat cag gaa cgc aca gat gat g.
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Vg gene activation by amino acid depends upon electrochemical gradients required for amino acid transport
Many amino acid transporters require electrochemical gradients across
membranes to function. Therefore, we used the
Na+/K+-ATPase inhibitor ouabain (10-5 mol
l-1) and the V-ATPase inhibitor bafilomycin A1 (10-6 mol
l-1) to shut down the Na+ and the proton gradient,
respectively, at the plasma membrane of fat body cells. Treatment of the fat
bodies with both drugs resulted in a strong inhibition of AA-induced
vg gene expression (Fig.
2A). By contrast, ouabain and bafilomycin A1 did not inhibit the
upregulation of the early gene E74 after stimulation with 20E
(Fig. 2B).
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Cloning and characterization of two cationic amino acid transporter cDNAs from Aedes aegypti fat body
Next, we isolated the cDNAs of cationic AA transporters expressed in the
A. aegypti fat body. EST mining and BLAST analysis of the
Drosophila and Anopheles genome databases revealed two
potential proteins with homology to vertebrate cationic AA acid
transporters.
One of these, slimfast (slif), has been described in
Drosophila as a cationic AA transporter
(Colombani et al., 2003). The
A. aegypti slif (Aaslif) cDNA (AY654299) consists of 2256
nucleotides and codes for a protein consisting of 428 AAs with a predicted
molecular mass of 64 kDa. Aaslif is 68% identical to a predicted
An. gambiae homologue (XM_314535) and 52% identical to D.
melanogaster slif. Protein folding prediction algorithms predicted that
Aaslif contains a total of 14 trans-membrane helices.
We cloned a second cationic AA transporter and named it Aedes aegypti insect cationic amino acid transporter 2 (AaiCAT2; DQ099901). We have chosen the name iCAT to clearly distinguish between the vertebrate CAT2 and the insect transporter. The iCAT2 cDNA consists of 2993 bp and encodes a protein of 605 AAs. The predicted molecular mass of iCAT2 is 66 kDa and it contains 14 trans-membrane helices. AaiCAT2 is 75% identical to its predicted An. gambiae homologue (EAA09874) and 46% identical to a predicted D. melanogaster homologue (AAF49292).
Phylogenetic analysis placed the insect CAT homologues in two groups that lie outside the well-characterized mammalian CAT1, 2 and 3 proteins (Fig. 3), indicating that variants of the mammalian CAT proteins probably arose from a common precursor after divergence from insects. In accordance with this, slif and iCAT2 are more closely related to each other than to any of the vertebrate CAT proteins.
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RNAi-mediated knockdown of cationic amino acid transporters results in strong inhibition of AA-induced vg gene expression
Various dsRNAs were injected into 1 day-old non-blood fed mosquitoes. After
5 days of recovery the mosquitoes were dissected and fat bodies were cultured
in the presence and absence of AAs. Relative levels of vg mRNA in the
fat bodies were determined using real-time PCR. Gene transcript knockdown was
confirmed by RT-PCR analysis (Fig.
5A,B)
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TOPSummaryIntroductionMaterials and methodsResultsDiscussionReferences |
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).
Furthermore, a high percentage of blood meal derived AAs are used for energy
production via oxidation or for energy storage via
gluconeogenesis and lipogenesis (Zhou et
al., 2004). In addition, AAs function as blood meal-derived
signaling molecules that affect the fat body-specific expression of yolk
protein genes via the nutrient sensitive TOR/S6K signaling pathway
(Hansen et al., 2004;
Hansen et al., 2005).
Here, we demonstrate that in A. aegypti, vitellogenic gene
expression is dependent upon a number of specific AAs. We tested the effect of
media lacking specific AAs versus a complete balanced AA medium on
vg gene expression in mosquito fat bodies
(Fig. 1). Interestingly, the
AAs found to be essential for vitellogenesis include the eight AAs shown to be
essential for growth in mammals (Rose,
1976) with the exception of isoleucine, which was on the
borderline for being essential for vitellogenesis. One AA found to be
essential for vitellogenesis, but not for mammalian growth was asparagine.
Comparison of AAs essential for A. aegypti vg gene expression and
those essential for complete egg development in A. aegypti and
Culex pipiens has revealed a high degree of conservation of the AAs
essential for these processes. The only exception again was asparagine, which
was found to be essential for vitellogenesis in this assay but not for egg
development when omitted from an artificial blood meal in Aedes
(Lea et al., 1956;
Uchida, 1992). Studies
examining the requirements of AAs for larval growth show that the same AAs
essential for vitellogenesis are also essential for larval growth
(Sing and Brown, 1957)
(Fig. 1).
Both cationic and branched chain AAs have been implicated in nutritional
signaling via the TOR kinase pathway, and leucine in particular has
been shown in a number of studies to be especially important
(Colombani et al., 2003;
Jacinto and Hall, 2003;
Kimball and Jefferson, 2004;
Lynch et al., 2000). The fact
that the lack of leucine has the greatest effect upon vg gene
expression provides further confirmation that the AA/TOR/S6K signaling pathway
is regulating this system. The results from the AA withdrawal experiments show
that exclusion of either arginine or lysine from the fat body severely
inhibits vitellogenic activation even when the other 19 AAs are present. Most
likely, these two AAs, as well as the other AAs found to be essential, are
working through a specific detection system linked to the TOR pathway. The
requirement of these specific AAs for nutritional signaling is likely
conserved in evolution.
A number of AAs were identified as non-essential for TOR-mediated
activation of vg gene expression in the mosquito fat body. Hemolymph
concentrations of some of these AAs may be high before a blood meal making
them poor signaling molecules. Indeed, proline, alanine and glutamic acid are
at a high concentration relative to the other free AAs in the hemolymph of
competent pre-blood fed mosquitoes
(Goldstrohm et al., 2003).
A. aegypti may use proline for nitrogen storage before and after
blood meal. This finding is in agreement with the fact that these AAs also
appear to be non-essential for vitellogenic activation.
The mechanism of how AAs activate the TOR pathway remains unknown. Amino
acids are taken up by cells via a specific system of plasma membrane
transporter proteins. The various transporters possess substrate selectivity.
Every transporter transfers a specific subset of AAs through the membrane. AA
transporters, if not a direct sensor for AAs are thought to be at least
indirectly involved in sensing AAs. There are four proposed general mechanisms
by which AA transport might regulate nutritional signaling. One possibility is
that the transporter acts as a receptor at the top of a signal transduction
pathway. In yeast, an AA-sensing protein, Ssy1, has been identified. While it
is not definite that this protein actually transports AAs, it is necessary for
detection and is structurally related to other AA transporters
(Poulsen et al., 2005). The
second possibility is that AAs flowing into and other solutes flowing out of
the cell results in physiological changes in membrane polarity, cellular
volume, pH and salt concentrations, which are then detected by the cell.
Changes in cell volume have been attributed to potentiate S6 kinase
phosphorylation in hepatocytes (Van
Sluijters et al., 2000). A third possibility is that an
intracellular receptor is detecting increased concentration of AAs, charged
tRNAs, or AA metabolites. In yeast the protein GCN2 (a regulator of the
translation factor eIF2B) is activated by uncharged tRNA
(Zhang et al., 2002). Fourth
and finally, if AAs are sensed by an extra cellular receptor, nearby
transporters affecting local extra cellular AA concentrations could regulate
these receptors by their level of transport activity. This type of mechanism
occurs in the central nervous system as seen when the neurotransmitter
glutamate is removed from the synaptic cleft due to rapid uptake by
transporters (Hand and Rouleau,
2002; Hyde et al.,
2003).
Many transporters are energized by electrochemical gradients along the
plasma membrane. These gradients are maintained by primary ATP-driven pumps,
such as V-ATPase, and secondary mineral ion transporters, such as
Na+/K+-ATPase
(Christensen, 1990). To test
our hypothesis that active AA transport into the fat body cells is necessary
to induce vg gene expression we disrupted the Na+ and
proton gradients at the fat body plasma membrane with specific inhibitors
(Fig. 2A). Bafilomycin and
ouabain inhibit membrane V-ATPase and Na+/K+-ATPase,
respectively. Thereby these drugs de-energize the plasma membrane and reduce
AA transporter activity in a manner similar to that of depletion of ATP
(Boudko et al., 2005).
Deenergizing the fat body plasma membrane by these inhibitors resulted in
inhibition of the AA-induced vg gene expression, suggesting that
active transport of AAs through the fat body plasma membrane is necessary for
the induction of vg gene expression. By contrast, neither inhibitor
inhibits the upregulation of the early gene E74 after the stimulation with 20E
(Fig. 2B). This indicated that
the active transport at the plasma membrane of fat body cells was selectively
required for the AA-induced vg gene expression.
Our previous work has shown, that in the fat body of Aedes aegypti
the AA signal is transduced to the vg gene via the TOR/S6K
signaling pathway (Hansen et al.,
2004; Hansen et al.,
2005). In Drosophila an amino acid transporter has been
identified as part of a nutrient sensor mechanism in the fat body that
controls global growth in the fly
(Colombani et al., 2003). This
transporter, slimfast (slif), is closely related to the
cationic AA transporter family of proteins (CATs) in mammals. CAT proteins are
defined as transporters exhibiting affinities and translocation rates for
cationic AAs, which are higher than or equivalent to those for other types of
AAs. There are different cationic AA transport systems and the CAT proteins
specifically are members of the y+ system of cationic transporters. The y+
system is specific for the basic AAs arginine and lysine. y+ transporters are
typically pH independent and transport activity is stimulated by membrane
hyperpolarization. These transporters are stimulated by the presence of amino
acids on the trans side of the membrane
(Closs, 2002;
Deves and Boyd, 1998).
Based on sequence homology we identified two CATs in the An.
gambiae and Drosophila databases and subsequently cloned the
A. aegypti homologues of these proteins. The first one is the
mosquito homologue to Drosophila slif
(Colombani et al., 2003) and
was therefore termed Aaslif. The second, so far undescribed CAT was
called AaiCAT2 for A. aegypti insect cationic amino acid
transporter 2. Phylogenetic analysis revealed that the two insect CATs (iCATs)
are more similar to each other than to the vertebrate CATs
(Fig. 3). The two iCAT and the
three vertebrate CAT families form separate phylogenetic clusters.
We determined the mRNA expression profiles of Aaslif and AaiCAT2 in fat bodies during the previtellogenic period and during the vitellogenic period (see Fig. 4A). The mRNA expression profiles are surprisingly different (Fig. 4B,C). The AaSlif mRNA level is highly elevated directly after emergence and drops to a basal level between 6 and 12 h post eclosion; it rises again at 48 h PBM and are still elevated at 72 h PBM, the last time point we measured. By contrast, AaiCAT2 mRNA levels stay at a basal level during the entire previtellogenic period but are elevated after activation of vitellogenesis by blood feeding. These differences suggest that these two transporters have different functions during metamorphosis and vitellogenesis. The presence of high levels of transcript for AaSlif in newly eclosed mosquitoes and low levels of expression during previtellogenic and postvitellogenic periods suggests that this protein plays a role in amino acid transport during development and metamorphosis rather then during mosquito reproduction. However, slif may play a role as amino acid sensor in adult female mosquitoes. By contrast, the expression profile of AaiCAT2 suggests that it has more of a functional role in the fat body in response to increasing levels of AAs in the hemolymph after a blood meal. Its expression increases significantly after blood feeding, indicating that the mosquito is responding to higher levels of hemolymph AAs by producing this transporter. Based on these results, we can hypothesize that the AaiCAT2 protein is produced after a blood meal to allow the fat body to absorb the AAs needed for yolk protein production during vitellogenesis.
To test if slif and iCAT2 are obligatory for AA signaling
to the mosquito fat body we performed RNAi knockdown experiments
(Fig. 5). We used dsRNA against
slif and iCAT2 alone and then in combination. We utilized
dsRNA against a neutral AA transporter (NAT)
(Jin et al., 2003) as a
control. Knockdown of either slif or iCAT2 causes a severe
reduction of the AA-mediated vg response. The knockdown effect is
similar to that of TOR inactivation by either rapamycin or RNAi and the effect
of S6 kinase knockdown (Hansen et al.,
2004; Hansen et al.,
2005). Downregulation of the cationic AA transporter slif
has been reported to affect TOR signaling in the Drosophila fat body
of (Colombani et al., 2003). By
contrast, knockdown of NAT did not cause any effect, indicating the
required specificity of both iCATs. Knockdown of both slif and
iCAT2 together had no stronger effect than knockdown of the single
transporter, indicating the lack of a synergistic action of these CATs. Thus,
both transporters probably have different specificity and may be responsible
for the uptake of different essential AAs that participate in signaling to the
fat body. A detailed analysis of protein expression levels and the specificity
of these two molecular carriers will help to assess this hypothesis.
In summary, the results presented in this paper stress the importance of AAs as signaling molecules for the onset of vitellogenesis in the mosquito fat body after a blood meal. Specific AAs are essential for successful activation of vitellogenic gene expression whereas others are not. Electrochemical gradients needed for active AA transport across the fat body plasma membrane are also required. Furthermore, we identified two CATs that are obligatory for this process. Further analysis of this system will provide insight into the molecular mechanics of mosquito reproduction and the reproduction of other blood feeding insects.
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Acknowledgments |
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Database Deposition: The sequences reported in this paper have been deposited in the GenBankTM database with the accession numbers AY654299 (AaSlif) and DQ099901 (AaiCAT2).
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Footnotes |
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Present address: Yale School of Public Health, Yale University, New Haven,
CT, USA
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References |
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TOPSummaryIntroductionMaterials and methodsResultsDiscussionReferences |
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