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1 Are Required for NF-
B Activation and Lipid Raft Recruitment of Protein Kinase C
Induced by T Cell Costimulation1
Divisions of
* Immunochemistry and
Immunogenetics, German Cancer Research Center (Deutsches Krebsforschungszentrum), Im Neuenheimer Feld, Heidelberg, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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B activation pathway induced by T cell costimulation uses
various molecules including Vav1 and protein kinase C (PKC)
. Because
Vav1 inducibly associates with further proteins including phospholipase
C (PLC)
1 and Src homology 2 domain-containing leukocyte
phosphoprotein of 76 kDa (SLP-76), we investigated their role for
NF-B activation in Jurkat leukemia T cell lines deficient for
expression of these two proteins. Cells lacking SLP-76 or PLC1
failed to activate NF-B in response to T cell costimulation. In
contrast, replenishment of SLP-76 or PLC1 expression restored
CD3/CD28-induced IB kinase (IKK) activity as well as NF-B DNA
binding and transactivation. PKC activated NF-B in SLP-76- and
PLC1-deficient cells, showing that PKC is acting further
downstream. In contrast, Vav1-induced NF-B activation was normal in
SLP-76- cells, but absent in PLC1- cells.
CD3/CD28-stimulated recruitment of PKC and IKK to lipid rafts was
lost in SLP-76- or PLC1-negative cells, while translocation of Vav1
remained unaffected. Accordingly, recruitment of PKC to the
immunological synapse strictly relied on the presence of SLP-76 and
PLC1, but synapse translocation of Vav1 identified in this study was
independent from both proteins. These results show the importance of
SLP-76 and PLC1 for NF-B activation and raft translocation of
PKC and IKK. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The SMAC includes active enzymes and also adapter proteins, which are
important for signal transmission, as they recruit signaling proteins
and help to regulate their conformation (5, 6). The
adapter Src homology 2 domain-containing leukocyte phosphoprotein of 76
kDa (SLP-76) contains several protein/protein interaction domains which
mediate contacts to various different binding partners such as
phospholipase C (PLC)1 and Vav1. Vav1 acts as a GDP/GTP exchange
factor for the Rho family of GTPases, thereby causing alterations in
cell shape and motility and stimulating various signaling pathways
(7, 8). Given the importance of SLP-76 as a scaffold
protein nucleating a multiprotein complex, mouse models show that this
adapter is critical for development, selection, and proliferation of
thymocytes (9). SLP-76-deficient Jurkat cells reveal its
importance for the activation of PLC1 induced by T cell
costimulation (10, 11). In addition, a direct interaction
between both proteins was shown (12). PLC1 activation
requires phosphorylation of at least two tyrosines and contact to the
adapter protein linker for activation of T cells (LAT), which probably
allows the juxtaposition of the two split catalytic domains to create a
contiguous catalytic center. Activated PLC1 cleaves the membrane
phospholipid phosphatidylinositol 4,5-bisphosphate into inositol
1,4,5-trisphosphate and diacylglycerol (DAG). While inositol
1,4,5-trisphosphate mobilizes Ca2+ from
intracellular stores, DAG mediates activation of protein kinase C (PKC)
family members (13). Among those, the novel
Ca2+-independent PKC isoform PKC is of special
importance for T cells, as it is almost exclusively expressed in
lymphoid cells and rapidly recruited to the SMAC. In addition, PKC
is required for proliferation of T lymphocytes and activation of
NF-B (14, 15).
NF-B is a collective term for inducible dimeric transcription
factors that comprise the Rel family of DNA binding proteins and is
involved in the activation of an exceptionally large number of genes
(e.g., IL-2 and IL-6) contributing to the regulation of the immune
response, apoptosis, and cell proliferation. In its inactive state,
NF-B is retained in the cytoplasm upon association with an
inhibitory IB protein. T cell costimulation induces phosphorylation
of IB by the IB kinase complex (IKC), which contains the IB
kinases (IKK) IKK
and IKK
and the regulatory subunit
IKK/NF-B essential modulator (NEMO) (16, 17).
Phosphorylated IB is readily ubiquitinylated and degraded by the
proteasome, thus resulting in the accumulation of NF-B in the
nucleus. Some members of the signaling cascade leading to NF-B
activation in T cells have been unequivocally identified by knockout
experiments. Apart from PKC, the absence of Vav1 (18)
or Bcl-10 (19) also prevents NF-B activation by T cell
costimulation.
Given the relevance of Vav1 and PKC for the activation of NF-B by
CD3/CD28 costimulation, we investigated the role of SLP-76 and PLC1
for NF-B induction and raft recruitment of PKC, Vav1, and the
IKC. Our data identify SLP-76 and PLC1 as essential components for
NF-B activation and lipid raft translocation of PKC and the IKC.
In addition, these experiments allow to order the sequence of some
early signaling steps in T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The Abs were obtained from the following: Vav1, Upstate
Biotechnology (Lake Placid, NY); PKC, BD Transduction
Laboratories (Lexington, KY) and Santa Cruz Biotechnology (Santa Cruz,
CA); IKK and LAT, Santa Cruz Biotechnology. TCR(CD3) (OKT3)
and CD28 (9.3) Abs have been purified from hybridomas. The
luciferase construct (B)3-Luc and expression vectors for flag-tagged
Vav1, PKC A/E, and PKC K/R were described (15). The
PLC inhibitor U73122 and the control compound U73343 were purchased
from Calbiochem (La Jolla, CA).
Cell culture, transfections, and stimulations
Jurkat T leukemia cells deficient and repleted for SLP-76
(J14-v-29 and J14-76-11, respectively) (10) or PLC1
(J1 and J1 WT-1) (19) or Jurkat wild type (E6.1)
were grown at 37°C and 5% CO2 in supplemented
RPMI 1640 medium; retransfected cells were cultured in the presence of
G418 (1 mg/ml). Cells were transfected by electroporation using a gene
pulser (Bio-Rad, Hercules, CA) at 250V/950 µF with constant amounts
of DNA. Costimulation of Jurkat cells was performed in a final volume
of 500 µl by adding CD3 (final concentration, 2 µg/ml) and
CD28 (final concentration, 5 µg/ml) Abs together with protein A
(10 µg/ml).
EMSAs and luciferase determination
Equal amounts of nuclear protein were tested for protein binding
to oligonucleotides containing a NF-B site as described
(15). Luciferase assays were performed according to the
manufacturer’s instructions (Promega, Madison, WI) and quantified in a
Duo Lumat LB 9507 (Berthold, Nashua, NH); results were normalized to
-galactosidase produced by a cotransfected Rous sarcoma
virus--galactosidase expression vector.
In vitro kinase assays and Western blotting
Cells were lyzed, followed by immunoprecipitation of IKK. The
kinase assay was performed with the washed precipitate essentially as
described (15) in a final volume of 20 µl of kinase
buffer containing 40 µM ATP, 5 µCi
[-32P]ATP, and the purified substrate
protein GST-IB 1–54(1–54). After 20 min, the reaction was stopped by
the addition of 5x SDS loading buffer, followed by denaturing SDS-PAGE
and autoradiography. For Western blotting, proteins separated by
SDS-PAGE were transferred to a polyvinylidene difluoride membrane using
a semidry blotting apparatus (Bio-Rad).
Subcellular fractionation
Jurkat cells (3 x 107) were collected by centrifugation and washed in PBS. The cell pellet was resuspended in 250 µl of buffer S1 (10 mM HEPES/KOH, pH 7.4, 38 mM NaCl, 1 mM PMSF, 0.2 U/ml aprotinin, 50 µg/ml leupeptin, 25 mM NaF, 1 mM sodium orthovanadate) and subjected to four freeze-thaw cycles. Nuclei were removed by centrifugation and membrane/cytoskeletal fractions were obtained after a 100,000 x g centrifugation step of cytosolic extracts. The supernatant of this step represents the S100 fraction, the membrane/cytoskeletal pellets were air-dried and resuspended in 6 M urea before the addition of SDS sample buffer.
Lipid raft isolation
Cells were stimulated for 8 min and washed once with ice-cold PBS. Cells were lyzed in cold TXNE (25 mM Tris-HCl pH 7.4, 1% Triton X-100, 150 mM NaCl, 5 mM EDTA, 1 mM sodium orthovanadate, 1 mM sodium molybdate, 50 µg/ml leupeptin, 0.2 U/ml aprotinin, and 1 mM PMSF). After a 20-min incubation on ice, lysates were homogenized with 10 strokes in a Dounce homogenizer (Wheaton Science Products, Millville, NJ). For pouring the density gradient, the 2-fold amount of 60% OptiPrep (Axis-Shield, Oslo, Norway) was added to a final concentration of 40%. This was overlaid with 2 ml of 27% (v/v) OptiPrep in TXNE and then 600 µl of TXNE were added at the top of the gradient. After centrifugation in a SW60 rotor (Beckman Instruments, Fullerton, CA) for 3 h at 150,000 x g and 4°C, fractions of 500 µl were collected from top to bottom. Proteins were precipitated with methanol/chloroform and further analyzed by immunoblotting.
Immunofluorescence
Cells were stimulated for 10 min with Polybead polystyrene beads
(Polysciences, Warrington, PA) coated with CD3 and CD28 Abs.
Cells were centrifuged in a Cytospin (Thermo Shandon, Pittsburgh, PA)
onto glass slides, fixed with 4% paraformaldehyde in PBS, and
permeabilized with 0.1% (v/v) Triton X-100 in PBS. After blocking with
5% (w/v) BSA in PBS, primary Abs were added for 1 h. After
extensive washing with PBS, cells were incubated with a chicken
anti-goat Alexa 488 Abs (Mobi-Tec, Göttingen, Germany), followed
by washing and incubation with a goat anti-mouse 633 Abs (Mobi-Tec).
Alexa 488-coupled cholera toxin (Alexa 488-CTx) was purchased from
Mobi-Tec. Cells were stimulated, fixed, and blocked as described before
adding the Alexa 488-CTx (4 µg/ml).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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1 lack peripheral T
cells, we investigated the role of both proteins for CD3/CD28-induced
NF-B activation in Jurkat cells deficient in SLP-76 (J14-v-29)
(10) or PLC1 (J1) (20). Jurkat cells
exhibiting high expression levels for CD3 and CD28 (data not shown)
were tested for induced NF-B DNA binding by EMSAs. Treatment with
agonistic CD3/CD28 Abs failed to induce DNA binding of NF-B in
cells lacking SLP-76 or PLC1 (Fig. 1
A), but occurred in the
retransfected SLP-76 (J14-76-11) and PLC1 (J1 WT-1) control
cells, demonstrating that this failure is due to the absence of SLP-76
or PLC1. Treatment of SLP-76- or
PLC1- cells with the PKC-activating phorbol
ester PMA (data not shown) or PMA in combination with ionomycin
elicited DNA binding of NF-B (Fig. 1A), showing that
these agents can bypass the early signaling events mediated by SLP-76
and PLC1. Because some NF-B activators selectively affect IKK
activation/IB degradation rather than NF-B-dependent
transcription (21, 22), we tested the relevance of SLP-76
or PLC1 for NF-B-dependent transactivation by reporter gene
assays. Costimulation of T cells induced NF-B-dependent
transcription only in repleted cells, but not in cells lacking
expression of SLP-76 or PLC1 (Fig. 1B). Activation of PKC
by phorbol ester either alone or in combination with CD3/CD28 ligation
allowed activation of NF-B-driven transcription also in the
deficient cells. To test the importance of SLP-76 or PLC1 for
CD3/CD28-induced IKK activity, cells were treated with CD3/CD28 Abs
either alone or together with PMA. CD3/CD28 stimulation failed to
induce IKK activity in cells lacking SLP-76 or PLC1, as revealed by
immune complex kinase assays (Fig. 1C). However, IKK
activation was restored in the presence of PMA. Stable expression of
SLP-76 or PLC1 in Jurkat cells allowed CD3/CD28-induced IKK
activation, thus identifying SLP-76 and PLC1 as essential components
of the NF-B signaling cascade triggered by T cell costimulation.
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within the NF-B
activation cascade, we tested the impact of transiently expressed Vav1
or PKC on NF-B-dependent transcription in deficient and repleted
cells. Vav1-induced activation of a NF-B-dependent reporter gene was
unaffected in SLP-76- cells. In addition,
expression of the constitutively active form of PKC (PKC A/E)
also triggered NF-B activity (Fig. 2A), which is in accordance
with the observed bypass function of PMA (see Fig. 1
). Surprisingly,
PKC A/E-induced NF-B transcription was reduced in SLP-76 repleted
cells. This might be taken as an indication that either SLP-76 itself
or an associated inhibitory protein such as Src-like adapter
protein-130 (23) provides a negative
signal in unstimulated T cells, thus preventing the onset of
an undesired immune response. Coexpression of Vav1 and PKC A/E
allowed synergistic activation of NF-B activity in
SLP-76- cells (Fig. 2A), showing that
the adapter is not required for the Vav1/PKC synergism. In
PLC1-deficient T cells, expression of Vav1 failed to induce NF-B
activity (Fig. 2B). This result is in accordance with the
finding that Vav1 acts upstream of PKC (15, 24) and
suggests that Vav1 is further upstream of PLC1 within the signaling
cascade. To test whether SLP-76 is required for Vav1-induced PKC
activation, we investigated the effect of a kinase-deficient point
mutant of PKC (PKC K/R) on Vav1-induced NF-B activation in
SPL76-deficient and retransfected cells. In both cell types,
Vav1-triggered NF-B activation was completely suppressed in the
presence of PKC K/R (Fig. 2C), thus placing Vav1 upstream
from PKC. In support to this model, Vav1-negative mast cells showed
impaired phosphorylation and activation of PLC1 (25).
Therefore, Vav1-triggered activation of NF-B seems to require
PLC1 and subsequent activation of PKC. Vav1 is known to trigger
Ca2+-dependent and -independent pathways
(7). However, its NF-B-inducing capacity does not seem
to rely on Ca2+ signals, because stimulation with
ionomycin could not rescue the defective IB degradation in Vav1
knockout cells (18). PKC-triggered NF-B
function was intact in PLC1-deficient cells. However, coexpression
of Vav1 and PKC failed to synergistically activate NF-B in
PLC1-negative cells (Fig. 2B), which is due to the
absence of a Vav1-derived stimulatory signal. Our results show that
Vav1 triggers PLC1, which subsequently is required for
PKC induction in the NF-B activation cascade in T cells.
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B activation? Because CD3/CD28-triggered recruitment of PKC to
the membrane is a prerequisite for its NF-B-activating function
(26), we investigated the contribution of SLP-76 to this
membrane translocation. Costimulation-induced membrane recruitment of
PKC was lost in SLP-76-deficient cells and occurred only in SLP-76
retransfected cells (Fig. 3A),
suggesting that the lack of membrane recruitment contributes
to the defect in NF-B signaling. In contrast, Ag-induced
membrane association of Vav1 was completely intact in
SLP-76- cells, indicating that binding of Vav1
to this adapter protein is not required for its membrane
localization. The same experimental approach in PLC1-deficient cells
revealed absent PKC recruitment to the plasma membrane (Fig. 3A). This indicates that the activating
function of PLC1 for PKC does not only rely on the production of
DAG, but also in its contribution to PKC membrane recruitment. In
contrast, CD3/CD28-induced relocalization of Vav1 to the membrane was
unaffected in PLC1- cells.
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to lipid rafts is required for
its proper function (15), we investigated its
translocation to these membrane microdomains. Extracts from
unstimulated or activated SLP-76-deficient and repleted cells were
fractionated by ultracentrifugation according to their buoyant density
and analyzed by immunoblotting. PKC was absent from lipid rafts in
untreated and CD3/CD28-stimulated SLP-76-
cells (Fig. 3B). Replenishment of SLP-76 expression allowed
induced translocation of PKC to lipid microdomains (Fig. 3B, fraction 2). Accordingly, CD3/CD28-induced PKC kinase
activity was found to be greatly impaired in SLP-76-deficient Jurkat
cells (27). Analysis of these fractions for Vav1
distribution revealed barely detectable Vav1 in the raft fraction of
unstimulated cells, but normal CD3/CD28-induced translocation of Vav1
to lipid rafts (Fig. 3B). Because rafts of activated human T
lymphocytes also contain enzymatically active IKKs (28),
the raft fractions were tested for the occurrence of the IKC component
IKK. The faint amount of IKK contained in the lipid raft fraction
of unstimulated cells was not further increased upon CD3/CD28
stimulation of SLP-76-deficient cells, while inducible translocation
was restored upon replenishment of SLP-76 (Fig. 3B),
revealing the necessity of SLP-76 for raft recruitment of PKC and
the IKC. Control experiments ensured that fraction 2 constitutes the
lipid raft fraction, as it was highly enriched in the constitutive raft
resident LAT (Fig. 3B) and in the ganglioside GM1 (data not
shown). A similar experimental approach was taken to explore the
relevance of PLC1 for lipid raft recruitment of these molecules.
CD3/CD28-induced lipid raft translocation of PKC and IKK required
PLC1 (Fig. 3C), thus demonstrating an important
additional function for PLC1. In contrast, raft association of Vav1
still occurred in the absence of PLC1, although replenishment of
PLC1 expression increased the efficiency of Vav1 recruitment (Fig. 3C). While this manuscript was in preparation, a study by
Villalba et al. (29) showed PLC1-independent raft
translocation of PKC. To test whether the enzymatic function of
PLC1 is important for PKC recruitment, CD3/CD28-induced
translocation was tested in the presence of the PLC1 inhibitor
U73122. This compound did not prevent raft translocation of PKC
(Fig. 3D) or IKK (data not shown), thus suggesting that
the relevance of PLC1 for recruitment is independent from its
enzymatic activity and rather relies on its function as a scaffold. It
has to be investigated in future studies whether the absence of IKK
raft transport also accounts for the defective NF-B activation in
SLP-76- and PLC1-deficient cells and if lipid raft localization of
the IKC is required for its proper function. Interestingly, other
members of the NF-B activation pathway such as Carma1
(30), as well as Bcl-10 and IKK, also move inducibly to
lipid rafts (O. Dienz and M. Lienhard Schmitz, unpublished results),
suggesting that recruitment of NF-B activators to these membrane
microdomains is of biological relevance.
To investigate the importance of SLP-76 and PLC1 for the transport
of PKC and Vav1 to the immunological synapse, we used
CD3/CD28-coated beads to mimic the effect of APC stimulation on T
cells (31). The functionality of this experimental system
was revealed by the accumulation of FITC-labeled CTx (FITC-CTx), which
binds GM1 gangliosides contained in lipid rafts, at the interphase
between the beads and T cells (Fig. 4A). Analysis of PKC
distribution by immunofluorescence in SLP-76-negative cells revealed a
lack of PKC aggregation at the synapse, as seen by the dispersed
staining over the cell surface (Fig. 4B). In contrast,
SLP-76-expressing T cells showed PKC localization in a dense cap
that contacted the stimulating bead. Accordingly, recruitment of PKC
to the synapse was strictly dependent on the presence of PLC1.
Analysis of Vav1 distribution by immunofluorescence in deficient and
repleted cells revealed localized clustering of Vav1 in the contact
region to the coated beads, demonstrating that also Vav1 is recruited
to the immunological synapse. However, this process was independent
from SLP-76 or PLC1 (Fig. 4B), thus showing that Vav1 and
PKC, albeit being constitutively associated and acting in
overlapping pathways, use distinct mechanisms for their membrane
recruitment. Lipid raft clustering requires Vav1-dependent cytoskeleton
reorganization (32), raising the possibility that raft
recruitment of Vav1 itself has to be accomplished on a different
pathway. A previous study proposed that ZAP-70-mediated tyrosine
phosphorylation of Vav1 and LAT facilitates the formation of a
Vav1-Grb2-LAT complex and thus targets Vav1 into glycolipid-enriched
microdomains (33). Alternatively, there may be additional
pathways leading to the membrane recruitment of Vav1.
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Acknowledgments |
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1-deficient and retransfected cell lines.
We gratefully acknowledge the perfect technical assistance of T.
Hamid and S. Rueffer. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. M. Lienhard Schmitz at the current address: Department for Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland. E-mail address: Lienhard.Schmitz{at}ibc.unibe.ch
3 Abbreviations used in this paper: SMAC, supramolecular activation complex; SLP-76, Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa; PLC, phospholipase C; LAT, linker for activation of T cells; DAG, diacylglycerol; PKC, protein kinase C; IKK, IB kinase; IKC, IB kinase complex; CTx, cholera toxin.
Received for publication May 21, 2002. Accepted for publication October 4, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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1 in an SLP-76-deficient T cell. Science 281:413.1 (PLC-1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-1 and NFAT. Mol. Cell. Biol. 21:4208. is required for TCR-induced NF-B activation in mature but not immature T lymphocytes. Nature 404:402.[Medline]
B by functional cooperation between Vav and PKC in T lymphocytes. J. Biol. Chem. 275:24547.B. Immunol. Res. 19:183.[Medline]
B activity. Annu. Rev. Immunol. 18:621.[Medline]
B pathways. Proc. Natl. Acad. Sci. USA 96:3035.B and neural tube closure. Cell 104:33.[Medline]
1 PLC-1 to T-cell antigen receptor-mediated signaling: reconstitution studies of a PLC-1-deficient Jurkat T-cell line. Mol. Cell. Biol. 20:9149. in cell survival and NF-B activation. Nature 406:86.[Medline]
B-independent control of NF-B activity by modulatory phosphorylations. Trends Biochem. Sci. 26:186.[Medline]
is required for TCR-induced T cell activation. Immunity 12:151.[Medline]
activation and calcium responses in mast cells. Mol. Cell. Biol. 21:3763. to membrane rafts is required for T cell activation. Nat. Immunol. 2:556.[Medline]
and NF-B activation in response to engagement of CD3 and CD28. J. Immunol. 166:5654. with a lipid raft-associated inhibitor of B factor kinase IKK complex plays a role in the activation of the NF-B cascade by TCR and CD28. J. Immunol. 165:6933. in T cells is mediated by a nonconventional, PI3-K- and Vav-dependent pathway, but does not absolutely require phospholipase C. J. Cell Biol. 157:253.B activation. Nat. Immunol. 3:836.[Medline]
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