Modulation of Nuclear Factor-κB by Human T Cell Leukemia Virus Type 1 Tax Protein: Implications for Oncogenesis and Inflammation

Abstract

Activation of the nuclear factor kappa B (NF-kappaB) transcription factor family by different stimuli, such as inflammatory cytokines, stress inducers, or pathogens, results in innate and adaptive immunity. While the main function of NF-kappaB is to promote the host's immune response, the NF-kappaB pathway is frequently dysregulated by invading viral pathogens. Human T cell leukemia virus type 1 (HTLV-1) is the causative agent of a fatal malignancy known as adult T cell leukemia (ATL) and an inflammatory disease named tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). HTLV-1 encodes an oncoprotein, Tax, which plays a significant role in the initiation of cellular transformation and the elicitation of the host's inflammatory responses. Here, we review current thinking on how Tax may affect both diseases through activation of NF-kappaB signaling.

Full text

Introduction
Many of the molecular alterations associ-
ated with carcinogenesis occur in cell signaling
pathways that regulate cell proliferation and
differentiation. HTLV-1 is the etiological agent
for ATL, an aggressive human T-cell malig-
nancy, and for inflammatory pathologies vari-
ously named as HTLV-1 associated myelopathy
or tropical spastic paraparesis (HAM or TSP)
(1–4). ATL develops in 2–5% of HTLV-1
infected individuals after a prolonged disease-
free period (5,6). This long latency for ATL
suggests that multiple discrete events in a
normal cell are subverted by HTLV-1 in the
virus process of cellular transformation. How
HTLV-1 transforms T cells remains incom-
pletely understood. However, the expression of
virus-encoded protein early in infection likely
plays an important role (7–9).
Abstract
Activation of the nuclear factor kappa B (NF-κB) transcription
factor family by different stimuli, such as inflammatory cytokines,
stress inducers, or pathogens, results in innate and adaptive immu-
nity. While the main function of NF-κB is to promote the host’s
immune response, the NF-κB pathway is frequently dysregulated by
invading viral pathogens. Human T cell leukemia virus type 1
(HTLV-1) is the causative agent of a fatal malignancy known as
adult T cell leukemia (ATL) and an inflammatory disease named
tropical spastic paraparesis/HTLV-1 associated myelopathy
(TSP/HAM). HTLV-1 encodes an oncoprotein, Tax, which plays a
significant role in the initiation of cellular transformation and the
elicitation of the host’s inflammatory responses. Here, we review
current thinking on how Tax may affect both diseases through acti-
vation of NF-κB signaling.
Key Words
Human T cell leukemia virus
(HTLV-1)
Adult T cell leukemia (ATL)
HTLV-1 Tax
NF-κB
IKK
NIK
Inflammation
Kuan-Teh Jeang
Building 4, Room 306
9000 Rockville
Pike, Bethesda, MD 20892-0460
E-mail: kjeang@niaid.nih.gov
1
© 2006
Humana Press Inc.
0257–277X/
(Online)1559-0755/06/
34/1:1–12/$30.00
Modulation of Nuclear Factor-κB
by Human T Cell Leukemia Virus
Type 1 Tax Protein
Implications for Oncogenesis and Inflammation
Immunologic Research 2006;34/1:1–12
Jean-Marie Peloponese Jr.
Man Lung Yeung
Kuan-Teh Jeang
Molecular Virology Section,
Laboratory of Molecular
Microbiology National Institute of
Allergy and Infectious Diseases,
National Institutes of Health
Bethesda, Maryland 20892-0460

HTLV-1 encodes several regulatory pro-
teins in its pX region located between Env and
the 3′LTR; these proteins are translated from
four partially overlapping open reading
frames (ORF) including p12I(ORF-1), p13II
(ORF-2), p30II (ORF-2), Rex (ORF-3), and
Tax (ORF-4) (10). Among these proteins, Tax
is a potent transcriptional activator that drives
the transcription of all HTLV-1 transcripts
from the viral LTR. Tax activates LTR-
directed transcription by recruiting members
of the CRE-binding/activating transcription
factors (CREB/ATF) family to the viral pro-
moter (11). In addition, Tax activates other
cellular transcription factors such as nuclear
factor kappa B (NF-κB) and activator protein-
1 (AP-1), promoting accelerated cell prolif-
eration and cell survival (12).
There is conclusive evidence including
results from transgenic mice that the 40-kDa
nuclear HTLV-1 Tax protein is the entity
responsible for cellular transformation
(8,13,14). When expressed singularly, Tax is
sufficient to immortalize primary human T
lymphocytes and to transform rodent cells
(9,15). In part, cellular transformation by
HTLV-1 is explained by Tax’s ability to dereg-
ulate cellular signaling pathways and perturb
cellular gene expression (16). Tax can also
override normal cell cycle controls via multi-
ple means including transcriptional activation
and direct binding to cell cycle regulators
(17). Specifically, Tax upregulates the expres-
sion of several cyclins (cyclin C, D2, and E)
and CDK inhibitors such as CDK2, CDK4,
and p21Waf1/Cip1 (8). In addition, HTLV-1
infected cells avoid growth arrest and/or
apoptosis because Tax inhibits the functions
of the p53 tumor suppressor (18). En toto, Tax
utilizes multiple mechanisms from activation
of pro-proliferation genes to dysregulation of
checkpoints and DNA damage repair path-
ways to influence genomic instability, which
may form the basis for transformation (13). In
this review, we limit our focus to the role of
Tax-activation of NF-κB and discuss, in a
non-exhaustive manner, how this activity
relates to oncogenesis and inflammation.
The NF-κB Pathways
First described over 20 yr ago, the nuclear
factor kappa B (NF-κB) family of transcrip-
tional factors comprises a group of important
regulators of innate and adaptive immune
response (19,20). NF-κB promotes the
expression of well over 100 target genes,
including cytokines and chemokines, recep-
tors for immune recognition, and proteins
involved in antigen presentation (13,21,22).
NF-κB is viewed as a central mediator of
immune responses (20,23). Gene knockout
studies have established roles for NF-κB in
the ontogeny of the immune system and at
multiple steps during normal and abnormal
cellular proliferation as well as in cell survival
and programmed cell death (24–28). Perhaps
because it sits at the nexus of multiple path-
ways, NF-κB is frequently targeted by viral
pathogens that infect cells. Indeed, many
viruses exploit NF-κB in order to enhance
viral replication, host cell survival, and eva-
sion of immune responses.
The NF-κB family contains five members:
NF-κB1(p105/p50), NF-κB2(p100/p52), RelA
(p65), RelB, and cRel (Fig. 1) (19,29,30).
RelA , RelB, and cRel are expressed as tran-
scriptionally active proteins, whereas NF-κB1
and NF-κB2are synthesized as precursor pro-
teins that are processed to counterpart smaller,
transcriptionally active subunits, p50 and p52,
respectively (19,29,30). NF-κB members have
an approx 300-amino-acid Rel-homology
domain (RHD) at their amino-termini that con-
tain sequences used for dimerization, DNA
binding, nuclear transport (NLS), and interac-
tion with the cytoplasmic inhibitory IκB pro-
teins (Fig. 1) (19,30,31). With the exception of
Peloponese, Yeung, and Jeang
2

RelB, NF-κB proteins form homo- and het-
erodimers when activated. Examples include a
p50/52 heterodimer, which lacks transcrip-
tional activation domains, and a p50/p65 het-
erodimer, which is transcriptionally competent.
NF-κB is inactive in the cytoplasm of
latent or unstimulated cells because of its
association with inhibitors of kappa B (IκB)
proteins (Fig. 2) (21,29,32). IκB proteins
include IκBα,IκBβ,IκBε, Bcl-3, and C-ter-
minal subunits of p105 (NF-κB1) and p100
(NF-κB2) (32,33). IκB proteins conserve
ankyrin-like repeat domains, which regulate
the subcellular localization of Rel-NF-κB
Modulation of Nuclear Factor-κB3
Fig. 1. Schematic representations of NF-κB and IκB family members. (A) NF-κB family members are
characterized by a Rel Homology Domain (RHD) important for DNA binding, dimerization, and nuclear
localization. p105 and p100 are processed by the proteasome (processing site is indicated by arrow) to give
rise to the NF-κB proteins p50 and p52 respectively. (B) IκB family contains a series of ankyrin repeats that
allow for interaction with the RHD of NF-κB. (C) IKKα(IKK1) and IKKβ(IKK2) contain N-terminal kinase
domains, central leucine zippers, and a C-terminal helix-loop-helix domain. IKKγ/NEMO contains an N-ter-
minal α-helix (α), two coiled-coil domains, and a C-terminal zinc finger. Transactivation domain (TAD),
leucine zipper (LZ), glycine rich region (GRR), leucine zipper (LZ), helix-loop-helix (HLH), coiled-coil (CC),
and zinc finger (ZF).

proteins by masking the NLS, located in the
latter’s RHD (34–37). The IκB proteins show
different affinity and specificity for NF-κB
dimers. For example, IκBβinhibits the
p50/p65 heterodimer more efficiently than
the p50/RelB or p50/cRel complexes. By
contrast, IκBαrecognizes all three com-
plexes similarly.
Cytoplasmic NF-κB complexes can be
activated by a variety of stimuli, including
viral and bacterial pathogens, cytokines, and
stress-inducing agents, through two discrete
signaling routes: the canonical and non-
canonical pathways (Fig. 2) (21,29,32). The
canonical pathway is governed by an IκB
kinase (IKK) complex that phosphorylates
IκB molecules (32,38). The IKK complex
consists of three subunits: the enzymatic
IKKα, IKKβ, and the regulatory IKKγ(also
termed the NF-κB essential modulator
Peloponese, Yeung, and Jeang
4
Fig. 2. Mechanisms of Tax activation of the canonical and non-canonical NF-κB pathways. The canon-
ical pathway (right) consists of IKK-mediated phosphorylation, ubiquitination, and degradation of IκB pro-
teins leading to ubiquitination and degradation by the proteasome, and the nuclear translocation of RelA and
c-Rel-containing heterodimers. Tax activates the canonical pathway through its interaction with IKKγ. Tax
may recruit upstream activators to trigger IKK activation such as PI3K. The non-canonical pathway (left
panel) consists of NIK and IKKα-mediated p100 processing and nuclear mobilization of RelB/p52 het-
erodimers. Tax triggers activation of this NIK-downstream pathway by activating and recruiting IKKαto p100
stimulating phosphorylation, ubiquitination, and processing to p52.

[NEMO]) subunit (39–44). IKK phosphory-
lates specific serines (S32 and S36) in the N-
terminus of IκB, targeting the phosphorylated
moieties for ubiquitination and proteasomal
degradation and compelling IκB molecules to
release otherwise sequestered NF-κB pro-
teins. After being activated, NF-κB translo-
cates to the nucleus, where it stimulates
transcription of genes containing the consen-
sus sequence 5′-GGGRNNYYCC-3′(R is a
purine,Y is a pyrimidine, and N is any nucleic
acid) (Fig. 2) (45).
The non-canonical pathway does not
require the complete IKK complex but does
utilize IKKαand the NF-κB inducing kinase
(NIK) (46,47). In this pathway, unprocessed
full-length NF-κB2 (p100) can dimerize with
RelB and act as a cytoplasmic IκB molecule
preventing the nuclear translocation of RelB.
In this setting, proteolytic processing that
cleaves the ankyrin repeats removes p100’s
IκB function while generating an active
RelB/p52 complex, which can then translo-
cate into the nucleus (Fig. 2) (46,47).
RelB/p52 dimers recognize a novel NF-κB
sequence (5′-RGGAGAYTTR-3′, where R is
a purine and Y is a pyrimidine) (48). In gen-
eral, the canonical pathway is considered to
be important for the generation of inflamma-
tory and adaptative immune responses,
whereas the non-canonical NF-κB pathway
largely serves specific cell types such as B
lymphoid stromal cells and contributes to B-
cell maturation.
HTLV-1 Co-opts the Cell’s Canonical
NF-κB Pathway
Canonical NF-κB activation in T cells is
generally transient. Brief NF-κB activation
required for proliferation and survival of stim-
ulated T-cells is achieved through strictly
controlled feedback regulation. Hence, upon
stimulation by antigen, the T-cell receptor
(TCR) and its proximal signaling molecules
are downregulated to prevent sustained sig-
naling through the cell surface receptor. Fur-
thermore, activation of NF-κB induces the
expression and de novo synthesis of IκBα
which can enter the nucleus and halt NF-κB’s
transcriptional function. In distinction to its
strict physiologically regulated control, the
NF-κB family of transcription factors are
known to be constitutively activated in vari-
ous human malignancies, including leukemias
(49), lymphomas (50,51), and solid tumors
(52). Of relevance to this review, HTLV-1
transformed T cell lines and freshly isolated
ATL cells both show persistently unchecked
activation of NF-κB (53,54). In transformed
cell lines, Tax is the intracellular NF-κB
inducer. However, in cells from ATL patients,
NF-κB remains activated despite the eventual
shut-down of Tax expression, suggesting that
Tax may be needed to initiate but not to main-
tain NF-κB activation (55). In a recent study,
Higuchi et al. (56) proposed that CD30 can
play a role in Tax-independent activation of
NF-κB. CD30 is a member of the tumor
necrosis factor (TNF) receptor superfamily
and is used as a marker of malignancy in
Hodgkin’s lymphoma (HL) (57). Overex-
pression of CD30 in HL cell contributes to
constitutive NF-κB activation in these cells.
Similar to HL cells, ATL cells line and fresh
ATL cells also show elevated expression of
CD30 (56).
Different models have been proposed to
explain how Tax activates NF-κB. Initially, it
was thought that Tax directly interacted with
a latent NF-κB/IκBαcomplex to trigger acti-
vation (58). Following the identification of
IKK-mediated phosphorylation of IκBα,it
was reconsidered that Tax might activate NF-
κB by signaling through the IKK complex
(58). Indeed, inside cells, expression of Tax is
closely followed first by the phosphorylation
and then the degradation of IκBαand IκBβ
Modulation of Nuclear Factor-κB5

(58). A clue to how Tax interdigitates with the
IKK complex came from the unexpected find-
ing that this viral oncoprotein failed to acti-
vate NF-κB in either IKKγ–/– knocked-out
mouse embryonic fibroblasts or in mutant
Jurkat T-cells inactivated for IKKγ(59). A
mechanistic explanation was offered by the
discovery that Tax physically associates with
IKKγin mammalian cells (58,60), and that
Tax/IKK association causally activated NF-
κB (61).
Extensive mutagenesis studies have defined
several Tax point mutants that cannot activate
NF-κB (62,63) When investigated further, it
was verified that Tax point mutants inactive for
NF-κB were also unable to bind IKKγ(9,64).
Tax was found to associate directly with the
201–250 region in IKKγ(60,61). Interest-
ingly, while IKKγ’s function is also triggered
by proinflammatory cytokines (60,61), such as
TNFα, this latter activity maps to a C-terminal
zinc finger domain in IKKγseparate from its
Tax-relevant site. Thus, signaling through
IKKγby viral oncoprotein or cytokine appears
to be discrete and independent (60).
Recent studies by Jeong et al. (65) and
Tanaka et al. (66) provide insights into the
mechanism employed by Tax to active NF-
κB using kinase(s) upstream of IKK. In this
regard, Tax appears to interact with an
upstream kinase in the phosphatidylinositol-
3-kinase (PI3K)/Akt pathway. The PI3K/Akt
signaling pathway is activated by numerous
growth-factor and immune receptors and
regulates fundamental cellular functions
such as transcription, translation, prolifera-
tion, growth, and survival (67,68). Akt, also
called protein kinase B (PKB), is a Ser/Thr
kinase bearing some homology with protein
kinase C (PKC) and protein kinase A (PKA).
Akt is the cellular homolog of the viral onco-
protein v-Akt, which is responsible for a sub-
population of leukemias in mice (69).
Activated Akt modulates the function of
numerous substrates related to cell prolifer-
ation such as glycogen synthase kinase-3
(GSK-3), cyclin-dependent kinase inhibitors
P21Waf1/Cip1 and P27Kip2, and mammalian
target of rapamycin (mTOR) (67,68). Akt
also phosphorylates and activates IKKα,
which, in turn, phosphorylates IκBα, target-
ing it for degradation (70). Perturbation of
the PI3k/Akt pathway has been associated
with the development of diseases such as
cancer, diabetes, and autoimmunity
(67,71,72). Recently, Jeong et al. (65) sug-
gested that Akt is activated in HTLV-1-trans-
formed cells and that NF-κB activation is
linked to Tax activation of Akt. Interest-
ingly, inhibition of endogenous Akt with the
PI3K/Akt inhibitor LY294002 or anti-Akt
siRNA in Tax-expressing cells not only pre-
vented NF-κB activation but also impaired
p53 regulation. These findings suggest that
Akt plays a role in the activation of pro-sur-
vival pathways in HTLV-1-infected cells,
possibly through NF-κB activation and inhi-
bition of p53. Interestingly, Tanaka et al. (66)
showed that independent of Akt activation,
the 3-phosphoinositide-dependent protein
kinase-1 (PDK1) directly phosphorylates
IKKβat Ser 181 to induce NF-κB activation.
Direct phosphorylation of p65 in response
to proinflammatory cytokines and Tax pro-
vides another way for NF-κB activation.
O’Mahony et al. (73) showed that IKK phos-
phorylates p65 on S529 and S536 in response
to TNFαtreatment. Tax expression also
enhances IKKα-mediated p65 phosphoryla-
tion. Phosphorylation of Ser536 is required
for a complete NF-κB-response to Tax,
whereas phosphorylation of Ser529 appears to
be less important for Tax responsiveness (73).
Thus, Tax can not only modulates upstream
degradation of IκB in the cytoplasm, but can
also facilitate transcriptionally proximal
nuclear modifications of p65 to maximize the
activation of NF-κB target genes.
Peloponese, Yeung, and Jeang
6

Tax and the Non-canonical
NF-κB Pathway
Unlike the canonical pathway, non-canoni-
cal NFκB activation occurs in B cells and lym-
phoid stromal cells. Until now, a very limited
number of p100 processing inducers [lym-
photoxin beta (LT-β) (47,74), B-cell activating
factor (BAFF) (75,76), and CD40 ligand (77)],
tumor necrosis factor (TNF)-like weak inducer
of apoptosis (TWEAK) (78) and receptor acti-
vator of NF kappa B ligand (RANKL) (79)
have been identified. Ligation of these induc-
ers to their cognate receptors activates NFκB-
inducing kinase (NIK). Activated NIK triggers
IKKαkinase activity by phosphorylating the
latter’s activation loop (80). In addition, NIK
also functions as an adaptor molecule that
enhances the binding of IKKαand p100 (80).
Once bound to p100, activated IKKγphos-
phorylates S99, S108, S115, S123, and S872
of p100 facilitating β-transducin repeat-con-
taining protein (β-TrCP)–mediated ubiquiti-
nation and proteasome-mediated degradation
(81). The newly form p52/RelB dimer then
translocates into the nucleus and activates
expression of target genes such as chemokines
BLC, ELC, and SDF-1 (48).
Under physiological conditions, processing
of p100 is tightly regulated. This is reflected
by the low ratio of p52 to p100 in resting cells.
Dysregulated expression of p52 leads to
severe abnormalities in lymphoid develop-
ment (75–77). Moreover, constitutive pro-
cessing of p100 has been linked to various
lymphomas and leukemia (82–85), including
ATL (86,87). It has been suggested that T-cell
transformation by HTLV-1 may correlate with
inappropriate induction of p100 processing by
Tax (86). Tax physically interacts with two
short amino-terminal helices (αA and αB) in
p100 (86,88). Like NIK, Tax is thought to act
as an adaptor protein that assembles an
IKKα/p100 complex (80). Either NIK- or
Tax-mediated IKKαbinding to p100 requires
a recognition site formed by the latter’s serine
866 and 870. Subsequent to protein-complex
assembly, phosphorylation of p100 by IKKα
triggers the ubiquitination and processing of
p100 by the 26s proteasome (80). Of note,
IKKγis also required for Tax-induced p100
processing. It is hypothesized that IKKγacts
as an adaptor for Tax to recruit IKKαto p100
(Fig. 2) (61,64,89–91). Hence, in the absence
of IKKγ, neither Tax’s activation of the canon-
ical NF-κB pathway nor Tax’s induction of
non-canonical p100 processing (86) occurs.
While NIK-induced p100 processing
depends absolutely on β-TrCP, this mechanism
only partially explains Tax-induced p100 pro-
cessing (92). It is noteworthy that increasing
p100 nuclear translocation also enhances its
processing. This suggests that p100 could be
processed in the nucleus through a yet identi-
fied mechanism (93). Since Tax is predomi-
nantly a nuclear protein that binds p100
(86,88), the above finding suggests that Tax
might ferry p100 into the nucleus facilitating a
nuclear β-TrCP-independent p100 processing.
HTLV-1 and Chronic Inflammation
HTLV-1 infection is associated with ATL
(6,94) and a chronic inflammatory disease
variously manifested as HTLV-1 associated
myelopathy/tropical spastic paraparesis
(HAM/TSP), HTLV-1 uveitis (HAU), HTLV-
1 associated arthropathy (HAAP), rheumatoid
arthritis, and dermatitis (4,95,96). While it is
not fully understood how HTLV-1 infection
causes chronic inflammation, it is believed
that the efficiency of the host’s CD8+cyto-
toxic T cell (CTLs) response to HTLV-1 plays
an important role in determining the proviral
load of HTLV-1 and a consequential chronic
inflammatory outcome (97). Interestingly,
most of the CTL response in an infected indi-
vidual is directed to the Tax protein (97,98).
Modulation of Nuclear Factor-κB7

The main roles of CD8+cytotoxic T cells
during viral infection are to eliminate infected
cells and to suppress viral replication by pro-
ducing inflammatory cytokines such as inter-
feron-γ(IFNγ) or tumor necrosis factor-α
(TNFα). Infiltrations of CD8+ T cells have
been found in inflammatory lesions in patients
with HAM/TSP (99). It is widely assumed
that tissue damage observed in the HTLV-1
associated inflammatory diseases such as
HAM/TSP is due to bystander damage caused
by the infiltrating lymphocytes. In their model,
Asquith and Bangham (100), proposed that in
patients with HAM/TSP, Tax expressing CD4+
T cells infiltrate the CNS and attract pro-
inflammatory CD8+T cells. Because of the
high viral load and the presence of abundant
Tax antigen, CTLs can simultaneously kill
the target cells and produce inflammatory
cytokines, resulting in collateral damage to the
CNS tissue (98,100). A recent transgenic
mouse study by Kwon et al. (101) provides
strong support for this model. Kwon et al.
(101) generated mice conditionally expressing
two different Tax mutant, Tax M22 and Tax
M47, which have NF-κB–/CREB+and NF-
κB+/CREB–functional phenotypes, respec-
tively. They observed that Tax and Tax M47
but not Tax M22 transgenic mice developed a
progressive dermatitis. The skin lesions were
characterized by the infiltration of T cells and
the local increase of inflammatory cytokines
such as TNFα, IL-6, IL-1α, IL-1β, lympho-
toxin-βand IFNγ. Of note, many of those
genes are NF-αB inducible chemokines. Inter-
estingly, similar inflammatory changes have
been observed in mice with up-regulated NF-
κB signaling (102).
Conclusion
Since the HTLV-1’s discovery 25 yr ago
(6,94), significant progress has been made
toward understanding the virus’ oncogenic
and inflammatory properties. Activation of
NF-κB plays an important role in the both
oncogenesis and inflammation. Through Tax,
HTLV-1 has devised multiple strategies to
activate efficiently both canonical and non-
canonical NF-κB pathways. Despite important
findings such as the identification of IKK as a
cellular target of Tax and an essential compo-
nent in Tax-stimulated NF-κB signaling, some
unanswered questions remain. How does
physical interaction of Tax with IKK trigger
activation of this kinase complex? What are
the role(s) of kinase(s) upstream of IKK such
as Akt or PDK1 in Tax-mediated NF-κB acti-
vation and in ATL progression? What are the
NF-κB downstream events that contribute to
Tax-related inflammation? These and other
questions will keep researchers busy for the
next 25 yr and beyond.
Acknowledgments
We thank members of the Jeang laboratory
for critical readings of manuscript. Our labo-
ratory is supported by intramural funds from
the NIAID, NIH. We apologize to investiga-
tors who we were unable to cite due to space
constraints.
Peloponese, Yeung, and Jeang
8
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