COMMUNICATION
IKK
Mediates the Interaction of Cellular I
B Kinases
with the Tax Transforming Protein of Human T Cell Leukemia
Virus Type 1*
Zhi-Liang
Chu
§,
Young-Ah
Shin
,
Jin-Ming
Yang
,
Joseph
A.
DiDonato¶, and
Dean W.
Ballard
§
From the
Howard Hughes Medical Institute and the
§ Department of Microbiology and Immunology, Vanderbilt
University School of Medicine, Nashville, Tennessee 37232-0295 and the
¶ Department of Cancer Biology, Lerner Research Institute,
Cleveland Clinic Foundation, Cleveland, Ohio 44195
 |
ABSTRACT |
The Tax oncoprotein of human T cell leukemia
virus type 1 constitutively activates transcription factor NF-
B by a
mechanism involving Tax-induced phosphorylation of I
B
, a labile
cytoplasmic inhibitor of NF-
B. To trigger this signaling cascade,
Tax associates stably with and persistently activates a cellular I
B
kinase (IKK) containing both catalytic (IKK
and IKK
) and
noncatalytic (IKK
) subunits. We now demonstrate that IKK
enables
Tax to dock with the IKK
catalytic subunit, resulting in chronic
I
B kinase activation. Mutations in either IKK
or Tax that prevent
formation of these higher order Tax·IKK complexes also interfere with
the ability of Tax to induce IKK
catalytic function in
vivo. Deletion mapping studies indicate that amino acids 1-100
of IKK
are required for this Tax targeting function. Together, these
findings identify IKK
as an adaptor protein that directs the stable
formation of pathologic Tax·IKK complexes in virally infected T cells.
 |
INTRODUCTION |
During an adaptive immune response, antigen-stimulated
CD4+ T lymphocytes become committed to an activation
program that triggers a transient phase of clonal expansion (1). In
contrast, infection with human T cell leukemia virus type 1 (HTLV-1)1 can lead to the
loss of cell cycle control and development of an aggressive malignancy
called adult T cell leukemia (2). The Tax oncoprotein encoded by HTLV-1
stimulates the constitutive nuclear expression of transcription factor
NF-
B, which regulates antigen-directed T cell proliferation (3, 4).
Studies with Tax-transgenic mice suggest that this viral/host
interaction is required to maintain the transformed phenotype of
HTLV-1-infected cells (5).
In quiescent T cells, the activity of NF-
B is controlled from the
cytoplasmic compartment by virtue of its signal-dependent interaction with inhibitors, including I
B
(6). Recent studies have identified two cytokine-inducible I
B kinases (IKKs), termed IKK
and IKK
, that target I
B
for degradation via
phosphorylation at Ser-32 and Ser-36 (7). These two kinases form
heterodimers and function as catalytic subunits within a 700-900-kDa
multicomponent complex (8). Whereas IKK
and IKK
are activated
transiently in cells treated with the cytokine tumor necrosis
factor-
(TNF) (8-10), Tax induces their constitutive expression in
HTLV-1-infected T cells (11, 12). We have recently found that
Tax-induced activation of both IKK and NF-
B requires the formation
of Tax·IKK complexes (12). However, the precise mechanism of Tax
action on IKKs remains unclear.
Here we provide several lines of experimental evidence indicating that
Tax-directed IKK activation is mediated by IKK
(also called NEMO,
IKKAP1, or FIP-3), a recently identified subunit of TNF-responsive IKKs
whose precise signaling function is unknown (13-16). First,
interference with IKK
expression in T cell transfectants inhibits
Tax-mediated activation of NF-
B. Second, IKK
and Tax interact
stably in the context of a high molecular mass I
B kinase derived
from HTLV-1-infected T cells. Third, overexpression of IKK
in
vivo is sufficient to target Tax specifically to ectopic IKK
,
whereas deletion of the N-terminal region of IKK
eliminates this
targeting function. The finding that IKK
enables Tax to dock with
cellular I
B kinases highlights an important missing link in the
mechanism by which this oncoprotein activates the constitutive
expression of NF-
B in HTLV-1-infected T cells.
 |
EXPERIMENTAL PROCEDURES |
Reagents--
Rabbit antisera specific for IKK
and Tax (amino
acids 321-353) have been described (13, 17). Anti-IKK
(H-744) and
IKK
(H-470) antibodies were obtained from Santa Cruz, Inc. Agarose beads conjugated to monoclonal anti-FLAG and anti-Myc antibodies were
purchased from IBI-Kodak and Santa Cruz, respectively. Expression vectors for antisense IKK
RNA (AS-IKK
) (14), Tax (17), FLAG epitope-tagged IKK
(10), and IKK
(13) have been described. Deletion mutants of IKK
were constructed by polymerase chain reaction using specific oligonucleotide primers (sequences available upon request) and subcloned into pcDNA3.1/Myc-His (Invitrogen). Chloramphenicol acetyltransferase (CAT) reporter plasmids contained either two tandem
B enhancers (
B-TATA-CAT) (18) or the HTLV1 5'
long terminal repeat (HTLV1 LTR-CAT) (19).
Cell Culture, Transfections, and CAT Assays--
Jurkat T cells,
RIP-deficient Jurkat T cells (20), HTLV-1-infected T cells (21, 22),
and S107 plasmacytoma cells (23) were cultured in RPMI 1640 medium
supplemented with 10% fetal bovine serum, 2 mM
L-glutamine, and antibiotics. Jurkat and S107 cells were
transfected via electroporation (24). Human 293T cells (25) were
transfected using calcium phosphate precipitation (26). All CAT assays
were performed as described (24).
Subcellular Fractionation and Biochemical
Analyses--
Cytoplasmic extracts were prepared by detergent lysis
(27) in the presence of phosphatase and protease inhibitors (12). For
gel filtration (9), cytosolic proteins (10 mg) were equilibrated in ELB
buffer (24) and subjected to chromatography on a precalibrated Superose
6 column (Amersham Pharmacia Biotech). Unless indicated otherwise,
immunoprecipitations were performed as described (12). Resultant
immunocomplexes were fractionated by SDS-polyacrylamide gel
electrophoresis and probed on polyvinylidine difluoride membranes using
an enhanced chemiluminescence system (SuperSignal, Pierce). I
B
kinase activity was measured as described using recombinant glutathione
S-transferase protein fused to amino acids 1-54 of I
B
(GST-I
B
) (9, 12).
 |
RESULTS AND DISCUSSION |
Constitutive Activation of NF-
B by Tax Involves IKK
but Not
RIP--
In prior studies, we established that Tax binds to and
persistently activates a TNF-responsive I
B kinase containing two
catalytic subunits termed IKK
and IKK
(12). To determine how Tax
interfaces with cellular IKKs, we first examined whether the Tax·IKK
signaling axis involves the death domain kinase RIP, which is essential for TNF-induced activation of NF-
B (20, 28). For these studies, Jurkat human T cells containing a RIP null mutation (20) were cotransfected with a Tax expression vector (Tax-WT) and a CAT reporter
plasmid containing two
B enhancers (
B-TATA-CAT). Parallel experiments were conducted with expression vectors containing point
mutations that selectively disrupt the ability of Tax to access either
the CREB/ATF (Tax-M47) or the NF-
B/Rel (Tax-M22) transcription
factor pathway (17). As shown in Fig.
1A, Tax-WT potently stimulated
NF-
B-directed transcription in both parental and RIP-deficient
Jurkat T cells. Similar results were obtained with Tax-M47 but not
Tax-M22, consistent with their differing capacities to activate
TNF-responsive IKKs (12). These in vivo functional data
clearly show that RIP is dispensable for Tax-induced activation of
NF-
B.

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Fig. 1.
IKK is required for
Tax-induced activation of NF- B in human T
cells. A, wild type or RIP-deficient (20) Jurkat T
cells (1 × 107) were cotransfected with B-TATA-CAT
(2.5 µg) and the indicated Tax expression vector (5 µg). Whole cell
extracts were prepared after 48 h and assayed for CAT activity.
Results from triplicate transfections are reported as the mean fold
induction (± S.E.) of CAT activity over basal levels in cells
transfected with B-TATA-CAT alone. B, Jurkat cells were
cotransfected with B-TATA-CAT or HTLV1 LTR-CAT (2.5 µg), a Tax
expression plasmid (5 µg), and the indicated doses of an antisense
IKK vector (AS-IKK ). Whole cell extracts were prepared after
48 h and assayed for CAT activity. For each titration point
(n = 3), results are expressed as the mean percentage
of CAT activity relative to that in AS-IKK -deficient cells (58- and
81-fold induction for B-TATA-CAT and HTLV1 LTR-CAT, respectively),
which was normalized to 100%.
|
|
RIP interacts specifically with IKK
, an integral subunit of
TNF-responsive IKKs (13-16). In this regard, Yamaoka et al.
(13) have reported experiments with IKK
-deficient rat fibroblasts, suggesting a requirement for this subunit in coupling Tax to NF-
B, whereas others (29) have identified an IKK
-deficient pre-B cell line
that is fully responsive to Tax. To determine whether IKK
couples
Tax to NF-
B in a more physiologically relevant setting, Jurkat T
cells were cotransfected with Tax-WT,
B-TATA-CAT, and graded amounts
of a vector that directs the synthesis of antisense IKK
RNA
(AS-IKK
). As shown in Fig. 1B, AS-IKK
inhibited
Tax-induced transcription directed from the NF-
B-responsive reporter
in a dose-dependent fashion. In contrast, interference with
IKK
protein expression failed to affect Tax-induced transcription
from the HTLV-1 5' long terminal repeat, which is activated by an
NF-
B-independent mechanism (30). These functional studies
demonstrate that IKK
is required for the induction of NF-
B by Tax
in the context of human T lymphocytes, the in vivo target
for HTLV-1.
Tax Interacts Stably with TNF-responsive IKKs Containing
IKK
--
IKK
assembles with TNF-responsive IKKs primarily via
its interaction with IKK
(13-15). This catalytic subunit also
associates with Tax in HTLV-1-infected T cells (12). To determine
whether IKK
is a core component of Tax-responsive IKKs, we first
performed in vitro kinase assays using cytoplasmic extracts
from SLB-1 and C8166 T cells. Whereas SLB-1 cells produce
replication-competent virions (21), C8166 cells harbor a defective
provirus that selectively expresses Tax (22). In these biochemical
experiments, Tax, IKK
, IKK
, and IKK
were isolated by
immunoprecipitation and assayed for IKK catalytic activity using a
GST-I
B
fusion protein as substrate. As shown in Fig.
2A (lanes 2-4,
top panel), GST-I
B
phosphorylating activity was
readily detected in Tax and IKK
·IKK
immunoprecipitates derived
from SLB-1 cells. A significant amount of IKK activity was also
detected in IKK
immunoprecipitates (lane 5). Similar
results were obtained with C8166 cells (Fig. 2A,
bottom panel). This subunit compositional analysis
establishes that IKK
is associated with a constitutively active
I
B kinase in both HTLV-1-infected and Tax-expressing T cells.

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Fig. 2.
IKK associates
stably with Tax-activated IKKs in HTLV-1-infected T cells.
A, subunit composition of constitutively active IKKs.
Cytoplasmic extracts (200 µg) from SLB-1 and C8166 cells were
subjected to immunoprecipitation with the indicated antisera. Resultant
immune complexes were incubated with GST-I B in the presence of
[ -32P]ATP. Phosphoproteins were resolved by
electrophoresis and visualized by autoradiography. B, size
distribution of Tax-associated IKKs. Cytosolic protein extracts (10 mg)
from SLB-1 cells were fractionated by gel filtration on Superose 6, and
the resultant eluates were subjected to immunoprecipitation with
anti-Tax antibodies. Immunoprecipitates were either analyzed for I B
kinase activity as described above (top panel) or probed on
immunoblots with anti-Tax antibodies (bottom panel). The
horizontal bar denotes the elution position of peak IKK
kinase activity derived from TNF-treated Jurkat cells. C,
IKK associates with Tax·IKK complexes. Pooled fractions
corresponding to peak IKK activity (panel B) were subjected
to immunoprecipitation with the indicated antisera, and the resultant
immune complexes were analyzed for either IKK kinase activity
(top panel) or Tax protein on immunoblots (bottom
panel). D, stability of IKK ·Tax complexes. Pooled
fractions corresponding to peak IKK activity (panel B) were
subjected to immunoprecipitation with IKK -specific antibodies.
Resultant immunocomplexes were washed three times with ELB buffer (24)
containing the indicated concentration (Conc.) of
dissociation agents and then assayed for either IKK kinase activity
(top panel) or Tax protein (bottom panel) as
described above.
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|
The TNF-responsive form of IKK that contains IKK
corresponds to a
700-900-kDa multisubunit complex (13, 14). To explore the size
distribution of Tax-associated IKKs, cytosolic proteins from
HTLV-1-infected SLB-1 cells were fractionated by gel filtration and the
resultant eluates were subjected to immunoprecipitation with anti-Tax
antibodies. Consistent with the size of TNF-responsive IKKs, the
majority of constitutively active IKKs associated with Tax in SLB-1
cells were detected in fractions corresponding to a molecular mass
exceeding 700 kDa (Fig. 2B). To determine whether IKK
was
also present in these Tax·IKK complexes, SLB-1 fractions containing
peak kinase activity were subjected to immunoprecipitation with
IKK
-specific antibodies and assayed for the presence of either IKK
activity or Tax protein. As shown in Fig. 2C, I
B kinase activity and Tax were readily detected in these IKK
immunoprecipitates (lane 3, top and bottom
panels). These biochemical data indicate that Tax associates with
IKK
in the context of a high molecular mass I
B kinase in
HTLV-1-infected T cells.
To address the stability of these higher order Tax·IKK
complexes,
IKK
was immunopurified from SLB-1 fractions containing peak kinase
activity (>700 kDa) and washed at high stringency with escalating
concentrations of NaCl and urea. We then monitored the dissociation of
IKK
·IKK
and Tax from these IKK
immunocomplexes using
in vitro kinase and immunoblotting assays, respectively. As
shown in Fig. 2D (bottom panel), high
concentrations of either dissociation agent failed to release Tax from
IKK
. Interactions between IKK
and the IKK
·IKK
catalytic
subunits were also highly resistant to release, as inferred from our
ability to detect significant levels of IKK
-associated I
B kinase
activity under identical washing conditions (Fig. 2D,
top panel). These results confirm that Tax, IKK
, and the
catalytic subunits of IKK interact with high affinity, further
underscoring the specificity and pathologic relevance of this
viral/host interaction in HTLV-1-infected T cells.
IKK
Mediates the Functional Interaction between Tax and
IKK
--
Tax activates TNF-responsive IKKs primarily via its
stimulatory effects on IKK
(11), which interacts directly with
IKK
(13-15). To determine whether IKK
directs the assembly of
Tax·IKK complexes, mammalian 293T cells
were transfected with expression vectors for FLAG-tagged IKK
,
IKK
, and Tax. Cytoplasmic extracts were then prepared and subjected
to immunoprecipitation with either monoclonal anti-FLAG antibodies
(Fig. 3A, top and middle panels) or
Tax-specific antibodies (Fig. 3A, bottom panel).
When IKK
immunocomplexes were probed on immunoblots for the presence
of Tax, we found that IKK
interacted weakly with Tax-WT, Tax-M22, and Tax-M47 in IKK
-deficient cells (Fig. 3A, lanes
2, 5, and 8, top panel). In
contrast, significant amounts of both Tax-WT and Tax-M47 were
associated with IKK
in cells coexpressing IKK
(lanes 3 and 9). Under identical transfection conditions, Tax-M22 failed to interact appreciably with IKK
in the presence of ectopic IKK
(lane 6). This divergent result with Tax-M22 could
not be attributed to inefficient ectopic expression, because comparable amounts of IKK
and Tax protein were detected in each triple
transfection (Fig. 3A, lanes 3, 6, and
9, middle and bottom panels). Coupled with our prior observation that Tax-M22 is defective for binding to
endogenous IKKs (12), these data strongly suggest that IKK
confers
IKK
targeting specificity to Tax.

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Fig. 3.
IKK directs the
formation of active Tax·IKK complexes.
A, 293T cells (1 × 106) were cotransfected
with expression plasmids for FLAG-tagged IKK (1 µg), Myc-tagged
IKK (0.5 µg), and Tax (2 µg) as indicated. Ectopic IKK and
Tax were isolated from cytoplasmic extracts by immunoprecipitation
(IP) with anti-FLAG M2 (top and middle
panels) and anti-Tax (lower panel) antibodies,
respectively. Resultant immunocomplexes were analyzed for the presence
of either Tax or IKK on immunoblots as indicated in the right
margin. The position of immunoglobulin heavy chains (H)
is indicated. B, S107 cells (1 × 107) were
cotransfected with expression vectors for FLAG-tagged IKK , IKK ,
and Tax (5 µg each) as indicated. Ectopic IKK was
immunoprecipitated from cytoplasmic extracts as described above and
assayed for I B kinase activity (see Fig. 2A, legend). WT,
wild type.
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|
To explore the functional consequences of these higher order
interactions, expression vectors for IKK
, IKK
, and Tax were introduced into S107 plasmacytoma cell line. Importantly, S107 cells
harbor a genetic defect that impairs NF-
B expression (23), thus
providing a cellular background with minimal I
B kinase activity. Following transfection, ectopic IKK
was immunopurified from S107 cytoplasmic extracts and monitored for catalytic activity using an
in vitro kinase assay. As shown in Fig. 3B, all
three of the Tax constructs failed to stimulate IKK
kinase activity
in the absence of ectopic IKK
(lanes 2-4), whereas
overexpression of IKK
in cells harboring wild type Tax and Tax-M47
potently induced IKK
(lanes 6 and 8). In
contrast, Tax-M22 was unable to activate IKK
in the presence of
IKK
(lane 7), consistent with its defect in endogenous
IKK binding (12). These functional data correlate precisely with our
biochemical results demonstrating that IKK
directs the formation of
Tax-M47·IKK
but not Tax-M22·IKK
complexes in mammalian 293T
cell transfectants (Fig. 2B).
The N Terminus of IKK
Is Required for Tax Targeting to
IKK
--
Primary sequence analyses indicate that IKK
contains a
C-terminal leucine zipper domain, a central coiled-coil domain, and an
N-terminal domain with no apparent secondary structural features (13-16). To define the sequences in IKK
that mediate its Tax
adaptor function, Tax and FLAG-tagged IKK
were transiently expressed in 293T cells along with a panel of Myc epitope-tagged deletion mutants
of IKK
(Fig. 4A).
Cytoplasmic extracts were prepared from transfected cells and subjected
to immunoprecipitation with antibodies specific for each ectopic
protein. The resultant immunocomplexes were then probed for the
presence of Tax and IKK
protein on immunoblots. As shown in Fig.
4B, removal of C-terminal sequences either abutting or
encompassing the leucine zipper domain of IKK
(mutants D1 and D2)
had no detectable effect on the formation of IKK
·Tax and
IKK
·IKK
complexes (lanes 4 and 5,
top and middle panels). However, deletion of the
N-terminal region of IKK
(amino acids 1-100, mutant D3) completely
disrupted both of these interactions (lane 6, top
and middle panels). We consider these results to be
significant, because the three IKK
deletion mutants were comparably coexpressed with Tax in the cytoplasmic compartment (Fig.
4B, lower panels). Furthermore, parallel
experiments conducted with Tax-M22 confirmed the specificity of these
higher order interactions (Fig. 4B, lanes
7-12).

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Fig. 4.
The N terminus of IKK
is required for Tax·IKK targeting. A, schematic
representation of full-length and truncated forms of IKK . Relative
positions of the N-terminal region (N, closed
boxes), coiled-coil domain (shaded boxes), leucine
zipper (LZ, striped boxes), and C-terminal region
(C, open boxes) are shown. Designations and
deletion end points for each Myc-tagged mutant are indicated.
aa, amino acids. B, 293T cells (3 × 106) were cotransfected with expression plasmids for
FLAG-tagged IKK (3 µg), Tax (6 µg), and the indicated Myc-tagged
forms of IKK (1.5 µg). Proteins indicated in the left
margin were isolated from cytoplasmic extracts by
immunoprecipitation (IP) with antibodies specific for FLAG
(top two panels), Myc (third panel), or Tax
(lower panel) epitopes. Resultant immunocomplexes were
probed on immunoblots with either Tax- or IKK -specific antibodies as
indicated in the right margin. C, 293T cells
(1 × 106) were cotransfected with expression plasmids
for Tax (4 µg) and Myc-tagged forms of either wild type
(WT) or truncated IKK as indicated (4 µg each, see
panel A). Ectopic IKK was immunoprecipitated from
cytosolic extracts using agarose-coupled anti-Myc antibodies. Resultant
immunocomplexes were monitored for either IKK activity (top
panel) or IKK protein levels (bottom panel) using
the in vitro kinase assay and immunoblotting procedures
described in Fig. 2.
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|
To extend these findings with ectopically expressed IKK
, we
monitored the incorporation of the same IKK
mutants into endogenous IKK complexes. For these studies, 293T cells were transfected with
IKK
and Tax expression vectors, followed by immunoprecipitation of
ectopic IKK
from the corresponding cytoplasmic extracts. The resultant IKK
immunocomplexes were analyzed for the presence of
Tax-activated IKKs using an in vitro kinase assay. As shown in Fig. 4C (top panel), overexpression of wild
type IKK
alone yielded minimal endogenous IKK activity (lane
2). However, coexpression of Tax with IKK
led to potent
activation (lane 3). Consistent with their ability to target
Tax to ectopic IKK
, IKK
mutants D1 and D2 were fully competent to
mediate Tax activation of endogenous IKK catalytic activity
(lanes 4 and 5). In contrast, the N-terminal deletion mutant of IKK
failed to reconstitute a functional Tax·IKK signaling axis (lane 6). We conclude that the N terminus of
IKK
is required for stable integration of this subunit into
endogenous IKK, which in turn renders the holoenzyme susceptible to
persistent activation by Tax.
In summary, we have found that the IKK
subunit of TNF-responsive
IKKs is an essential core component of Tax-associated IKKs in
HTLV-1-infected T cells. Higher order complexes containing Tax, IKK
,
and the IKK
·IKK
catalytic subunits are highly resistant to
dissociation in vitro, underscoring the specificity of this pathologic viral/host interaction. In vivo reconstitution
experiments demonstrate that IKK
directs the assembly of
Tax·IKK
complexes, resulting in the persistent expression of I
B
kinase activity. Thus, IKK
functions in Tax-mediated IKK activation
at the level of Tax·IKK docking. By analogy, this targeting mechanism
may reflect an important role for IKK
in coupling TNF-responsive
IKKs to upstream physiologic activators, such as NIK and MEKK1
(31).
 |
ACKNOWLEDGEMENTS |
We thank Shoji Yamaoka, Alain Israel, Frank
Mercurio, David Rothwarf, Michael Karin, and Brian Seed for reagents.
 |
FOOTNOTES |
*
This work was supported by National Institutes of Health
Grant RO1 AI33839 (to D. W. B), by NCI, National Institutes of
Health Training Grant T32 CA09385 (to Z.-L. C.), and by the Howard
Hughes Medical Institute.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.
To whom correspondence should be addressed: Howard Hughes
Medical Inst., Vanderbilt University School of Medicine, 802 Rudolph Light Hall, Nashville, TN 37232-0295. Tel.: 615-343-1548; Fax: 615-343-5743; E-mail: dean.ballard{at}mcmail.vanderbilt.edu.
 |
ABBREVIATIONS |
The abbreviations used are:
HTLV-1, human T cell
leukemia virus type 1;
CAT, chloramphenicol acetyltransferase;
GST, glutathione S-transferase;
IKK, I
B kinase;
TNF, tumor
necrosis factor-
.
 |
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