Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA
Author for correspondence (e-mail: haowu{at}med.cornell.edu )
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Summary |
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Key words: TRAF, TNF, IL-1R/TLR, NF-B, AP-1
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Introduction |
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The TRAF proteins are characterized by the presence of a novel TRAF domain
at the C-terminus, which consists of a coiled-coil domain followed by a
conserved TRAF-C domain (Rothe et al.,
1994) (Fig. 1). The
TRAF domain plays an important role in TRAF function by mediating
self-association and upstream interactions with receptors and other signaling
proteins (Takeuchi et al.,
1996
). The N-terminal portion of most TRAF proteins contains a
RING finger and several zinc finger motifs, which are important for downstream
signaling events (Rothe et al.,
1995
; Takeuchi et al.,
1996
).
|
Many of the biological effects of TRAF signaling appear to be mediated
through the activation of transcription factors of the NF-B and AP-1
family. NF-
B promotes the expression of genes involved in inflammatory
and anti-apoptotic responses (Baeuerle and
Baltimore, 1996
; Beg and
Baltimore, 1996
; Liu et al.,
1996
). It is activated by the I
B kinase (IKK), which
consists of two kinase subunits, IKK
and IKKß, and a regulatory
subunit, IKK
/NEMO (DiDonato et al.,
1997
; Regnier et al.,
1997
; Zandi et al.,
1997
; Krappmann et al.,
2000
). Phosphorylation and degradation of I
B lead to the
release and translocation of NF-
B to the nucleus to activate
transcription (Stancovski and Baltimore,
1997
). AP-1 activity is stimulated by mitogen-activated protein
(MAP) kinases through either direct phosphorylation or transcription of AP-1
components (Karin, 1996
). MAP
kinases, which include Ser/Thr kinases such as JNKs/SAPKs, ERKs and p38s, are
at the downstream end of a three-tiered system that also contains MAP kinase
kinase (MAP2K) and MAP kinase kinase kinase (MAP3K). The stimulation of AP-1
activity by MAP kinases may elicit stress responses and promote both cell
survival and cell death (Shaulian and
Karin, 2001
).
As adapter proteins, TRAFs elaborate receptor signal transduction by
serving as both a convergent and a divergent platform. Therefore, different
TRAFs are created with their own specific biological roles. Their distinct
upstream and downstream signaling pathways may determine this specificity.
Recent structural and biochemical data have provided us with a much better
understanding of the upstream signaling mechanism of TRAFs. Many of the
current studies of TRAF downstream signaling focus on the activation of
NF-B and AP-1 transcription factors. However, accumulating evidence
points to the differential regulation of this apparently common downstream
pathway as well as to additional TRAF-specific pathways for eliciting
different biological functions. We further suggest that signaling-dependent
TRAF trafficking may be another crucial regulatory factor. This commentary
will focus on the common and distinct molecular mechanisms of TRAF-mediated
signal transduction. For complementary information, please refer to other
recent reviews on TRAFs and TNF receptors
(Wallach et al., 1999
;
Inoue et al., 2000
;
Locksley et al., 2001
;
Wajant et al., 2001
).
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Specific biological functions of mammalian TRAFs |
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Since its discovery, TRAF2 has become the prototypical member of the TRAF
family. The paradigm of TRAF-mediated NF-B and MAP kinase activation
was first demonstrated using both TRAF2 overexpression and a dominant-negative
phenotype of a TRAF2 derivative lacking the RING domain
(Rothe et al., 1995
;
Hsu et al., 1996b
;
Takeuchi et al., 1996
;
Duckett et al., 1997
;
Reinhard et al., 1997
;
Arch et al., 1998
). TRAF2
transcripts have been detected in almost every tissue
(Rothe et al., 1994
), making
TRAF2 the most widely expressed TRAF family member.
TRAF2 plays a cytoprotective role, which was demonstrated by the premature
death of TRAF2-deficient mice owing to severe runting. In addition,
TRAF2-deficient cells are highly sensitive to TNF-induced cell death
(Yeh et al., 1997). The lack
of TRAF2 or the expression of a dominant-negative form of TRAF2 only led to a
modest defect in TNF-induced NF-
B activation but resulted in a severe
reduction of JNK/SAPK activation (Lee et
al., 1997
; Yeh et al.,
1997
; Devin et al.,
2000
). Recent data suggest that TRAF2 is important for NF-
B
activation, but this role may be partially compensated for by the highly
related TRAF5 (see below) (Nakano et al.,
2000
). The sensitization to TNF-induced cell death in the absence
of TRAF2 must have been largely due to an NF-
B-independent mechanism
(Lee et al., 1997
;
Yeh et al., 1997
;
Lee et al., 1998
). One
possibility may be related to the failure to recruit other proteins such as
cellular inhibitors of apoptosis proteins (cIAPs) to the TNFR1 receptor
signaling complex in the absence of TRAF2
(Wang et al., 1998
;
Park et al., 2000
). TNF
toxicity through TNFR1 appears to contribute significantly to the survival
defects in TRAF2-deficient mice because a double deficiency in TRAF2 and TNFR1
resulted in increased survival (Yeh et
al., 1999
).
TRAF1, unlike TRAF2 and other TRAFs, does not have the N-terminal RING and
zinc-finger domains (Rothe et al.,
1994). TRAF1 expression is fairly restricted
(Rothe et al., 1994
;
Mosialos et al., 1995
) and can
be upregulated in lymphoid tumors and transformed lymphoid cells
(Durkop et al., 1999
;
Zapata et al., 2000
,
Zapata et al., 2000
). The
current data are consistent with the idea that TRAF1 is an NF-
B
inducible protein that protects cells from apoptosis and plays a role in the
feedback regulation of receptor signaling
(Speiser et al., 1997
;
Wang et al., 1998
;
Carpentier and Beyaert, 1999
;
Schwenzer et al., 1999
;
Nolan et al., 2000
). It
appears that TRAF1 works in conjunction with TRAF2 and cIAPs to fully suppress
TNF-induced apoptosis. This may be achieved through the direct suppression of
caspase activation in the TNFR1 signaling complex by cIAPs, which are
specifically recruited through TRAF1 and TRAF2
(Wang et al., 1998
;
Park et al., 2000
).
Although TRAF3 possesses a putative domain organization similar to TRAF2
and TRAF5, overexpression of TRAF3 did not activate NF-B
(Rothe et al., 1995
). In
contrast, it was reported that TRAF3 recruitment to LTßR led to cell
death (Force et al., 1997
),
and that both N- and C-terminal domains of TRAF3 negatively regulate
NF-
B activation induced by Ox40
(Takaori-Kondo et al., 2000
).
However, it has also been shown that there are a variety of mRNA species of
TRAF3 and that some splice variants do induce NF-
B activation
(van Eyndhoven et al., 1999
).
Similar to TRAF2-deficient mice, TRAF3-deficient mice have poor perinatal and
neonatal survival (Xu et al.,
1996
). However, despite the runting phenotype and the hypotrophy
of the spleen and thymus, which is similar to the phenotype displayed by
TRAF2-deficient mice, the immune system is fairly normal except in the
T-cell-dependent antigen responses (Xu et
al., 1996
).
The biological importance of TRAF4 was revealed by the gross tracheal
malformation displayed by TRAF4-deficient mice
(Shiels et al., 2000), which
suggested a parallel function of TRAF4 with the Drosophila Toll
pathway in body organization. Analysis of TRAF4 expression has also implicated
TRAF4 in the function of neural multipotent cells and epithelial stem cells in
adult mammals (Krajewska et al.,
1998
; Masson et al.,
1998
). Even though there is evidence that TRAF4 may interact with
several receptors in the TNF receptor superfamily
(Krajewska et al., 1998
;
Ye et al., 1999
,
Ye et al., 1999
), further
studies are required to elucidate the molecular pathway of TRAF4
signaling.
TRAF5 is considered to be a close functional and structural homologue of
TRAF2, and overexpression of TRAF5 can also activate NF-B and AP-1
transcription factors (Ishida et al.,
1996
, Ishida et al.,
1996
; Nakano et al.,
1996
). However, deletion of TRAF5 did not cause perinatal
lethality, perhaps owing to the more restricted expression pattern of TRAF5
compared with TRAF2 (Ishida et al.,
1996
, Ishida et al.,
1996
; Nakano et al.,
1996
). TRAF5 deficiency led to more specific defects in CD40- and
CD27-mediated lymphocyte activation, whereas TNF-mediated NF-
B
activation was not severely affected
(Nakano et al., 1999
).
Interestingly, TRAF2 and 5 double knockout animals did exhibit a severe
reduction in TNF-induced NF-
B activation, which suggests that TRAF5 and
TRAF2 are partially functionally redundant
(Nakano et al., 2000
).
TRAF6 possesses a unique receptor-binding specificity that results in its
crucial role as the signaling mediator for both the TNF receptor superfamily
and the IL-1R/TLR superfamily. As shown by targeted gene ablation, TRAF6 is
functionally important for both TRANCE-R-mediated osteoclast activation and
CD40 signaling (Lomaga et al.,
1999; Naito et al.,
1999
; Wong et al., 1999b), even though both CD40 and TRANCE-R can
also signal through TRAF2 (Pullen et al.,
1998
; Wong et al.,
1998
). In the IL-1R/TLR superfamily, lack of TRAF6 leads to
defective signaling by IL-1 and IL-18 as well as hypo-responsiveness to
bacterial lipopolysaccharides (LPS), the cell wall component of Gram-negative
bacteria, which signals through TLR4
(Lomaga et al., 1999
;
Naito et al., 1999
). These
observations place TRAF6 as an important player in innate immunity against
pathogens.
The functional divergence of TRAFs appears to correlate well with a
proposed evolutionary relationship among TRAFs in mammals and other organisms
on the basis of sequence conservation in the TRAF domain and gene structure
analysis (Grech et al., 2000)
(Fig. 1). In this hypothesis,
TRAF4 and TRAF6 precursors appear to have arisen earlier in evolution. We
propose that TRAF4 and TRAF6 may be functional descendents of dTRAF1 and
dTRAF2, which have been implicated in Toll signal transduction
(Zapata et al., 2000
,
Zapata et al., 2000
;
Shen et al., 2001
). This
argument points to the existence of a yet to be identified TRAF4-interacting
receptor. On the other hand, TRAF1, 2, 3 and 5 appear to be more recent
siblings in the TRAF family (Grech et al.,
2000
). This observation is supported by the similar
receptor-binding specificity of these four TRAFs towards the TNF receptor
superfamily (see below) and the lack of known homologues of these receptors
beyond mammals.
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Common and distinct signal transduction mechanisms up-stream of TRAFs |
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A common mechanism for the membrane-proximal event in TRAF signaling has
been revealed by the conserved trimeric association in the crystal structure
of the TRAF domain of TRAF2 (Park et al.,
1999; McWhirter et al.,
1999
). The structure contains a stalk of a trimeric coiled-coil
and a cap of trimerized TRAF-C domain with a novel anti-parallel
ß-sandwich fold, leading to a prominent mushroom shaped structure
(Fig. 3A). This trimeric
stoichiometry of TRAFs provides a structural basis for signal transduction
across the cellular membrane after receptor trimerization by trimeric
extracellular ligands in the TNF superfamily
(Banner et al., 1993
).
Interestingly, recent studies suggest that specific ligand-induced receptor
trimerization may be primed by non-signaling receptor pre-association prior to
ligand binding (Chan et al.,
2000
; Siegel et al.,
2000
). Thermodynamic characterization revealed the low affinity
nature of monomeric TRAF2-receptor interactions, which confirms the importance
of oligomerization-based affinity enhancement or avidity in receptor-mediated
TRAF recruitment (Ye and Wu,
2000
).
|
Structural and biochemical studies have shown that a single TRAF protein
recognizes diverse receptor sequences via a conserved mode of interaction but
with a range of different affinities. In several different TRAF2 complexes,
receptor sequences bind invariably to the surface groove on the TRAF-C domain
of TRAF2 in an extended conformation, making main chain hydrogen bonding
interactions with the edge of the ß-sandwich structure
(Park et al., 1999;
McWhirter et al., 1999
;
Ye et al., 1999
,
Ye et al., 1999
). The chain
direction of the receptor peptides allows the receptors to immediately latch
on to the TRAF-C domain after exiting from their transmembrane regions.
Although TRAF2-binding sequences from different receptors bear limited
sequence homology, their interactions with TRAF2 are preserved by a few
conserved structural contacts, as shown in the consensus (P/S/T/A)x(Q/E)E
(Ye et al., 1999
,
Ye et al., 1999
)
(Fig. 3B). A deviation from
this consensus, which bears the sequence of PxQxxD, is present in the human
Epstein-Barr virus LMP-1 protein and binds to the same surface of TRAF2 via
both similar and distinct features (Ye et
al., 1999
, Ye et al.,
1999
). Thermodynamic characterization further showed variable
affinities of TRAF2 with different receptor sequences, which are probably a
consequence of affinity modulations by non-conserved residues within and
beyond the core binding motif (Ye and Wu,
2000
) (Table
3).
|
Further structural analyses have also revealed how several different TRAFs
can recognize a single receptor. The amino-acid residues on the TRAF2 surface
used for receptor interactions are conserved among TRAF1, 2, 3 and 5,
explaining the overlapping specificity of these TRAFs for different receptors
(Park et al., 1999;
Ye et al., 1999
,
Ye et al., 1999
). However, an
identical sequence from CD40 exhibits alternative binding modes to TRAF2 and
TRAF3, suggesting that this conserved interaction may vary to some extent in
different TRAFs, which modulates the strengths of the interactions
(Fig. 3C). In the TRAF3
complex, receptor residues distal to the central core sequence also interact
with TRAF3, leading to the formation of a hairpin on the TRAF3 surface, which
contributes strongly to TRAF3 interaction
(Ni et al., 2000
).
The distinct mode of TRAF2 recruitment by TRADD was revealed by the crystal
structure of the TRAF2-TRADD complex (Park
et al., 2000) (Fig.
3D). The more extensive TRAF2-TRADD interface overlaps spatially
and therefore potentially competes with TRAF2-receptor interactions.
Biochemical characterization using surface plasmon resonance has shown that
the TRAF2-TRADD interaction is unique in two distinct ways. First, TRAF2 has a
significantly higher affinity for TRADD than for peptide motifs in direct
receptor interactions (Table
3), which leads to more efficient initiation of TRAF2 signaling by
TRADD. Second, TRADD has specificity for only TRAF1 and TRAF2, but not other
TRAF family members (Fig. 2A). It appears that TRAF1 and TRAF2 work in conjunction with associated caspase
inhibitors cIAPs to fully suppress TNF-induced apoptosis in the TNFR1
signaling complex (Wang et al.,
1998
; Park et al.,
2000
), leading to dominance of survival signaling for this
receptor under most circumstances.
TRAF6 directly interacts with CD40 and TRANCE-R, which are members of the
TNF receptor superfamily (Ishida et al.,
1996, Ishida et al.,
1996
; Pullen et al.,
1998
; Darnay et al.,
1999
). For the signal transduction of the IL-1R/TLR superfamily,
TRAF6 is indirectly coupled to receptor activation via IRAK and the IRAK-TRAF6
pathway in evolutionarily analogous to the Pelle-dTRAF pathway in
Drosophila (Liu et al.,
1999
; Zapata et al.,
2000
, Zapata et al.,
2000
; Shen et al.,
2001
). Even though biochemical characterizations suggest that
TRAF6-receptor and TRAF6-IRAK interactions differ from receptor recognition by
other TRAFs (Pullen et al.,
1998
; Darnay et al.,
1999
), elucidation of the molecular mechanism of TRAF6 upstream
interactions awaits further structural information.
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TRAF downstream signal transduction and regulation |
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The activation of both NF-B and AP-1 by TRAF6 in the IL-1 signaling
pathway appears to involve a MAP3K known as TAK1
(Yamaguchi et al., 1995
;
Ninomiya-Tsuji et al., 1999
)
and two adapter proteins TAB1 (Shibuya et
al., 1996
) and TAB2 (Takaesu
et al., 2000
). Upon stimulation, TRAF6 associates with endogenous
TAK1 and TAB1 (Ninomiya-Tsuji et al.,
1999
) and interacts with TAB2 following the translocation of TAB2
from the membrane to the cytosol (Takaesu
et al., 2001
). Activated TAK1 appears to phosphorylate NIK, which
in turn activates IKK (Shirakabe et al.,
1997
; Ninomiya-Tsuji et al.,
1999
) and initiates the MAP kinase pathway. Surprisingly, it has
been shown recently that ubiquitination plays an important role in TAK1
activation (Deng et al., 2000
;
Wang et al., 2001
,
Wang et al., 2001
). It
appears that as a RING-domain-containing protein, TRAF6 operates together with
a ubiquitin-conjugating enzyme system to catalyze the synthesis of unique
polyubiquitin chains essential for TRAF6 downstream signaling.
The ability of multiple TRAFs to activate NF-B and AP-1
transcription factors raises the question of how are the specific biological
functions of different TRAFs realized. We propose that the different signaling
pathways, such as those utilized by TRAF2 and TRAF6, may lead to preferential
activation of specific NF-
B and AP-1 components and therefore the
transcription of an overlapping but non-identical set of genes. In addition,
many TRAF-interacting proteins have been identified and shown to regulate the
activation of NF-
B and AP-1 in a TRAF-specific manner. For example, A20
is a TRAF1- and TRAF2-interacting protein
(Song et al., 1996
) that
inhibits NF-
B activation and regulates TNF-induced cell death responses
(Lee et al., 2000
). A complete
review of these regulatory proteins is beyond the scope of this commentary;
however, their potential functions should not be overlooked.
A different level of regulation was revealed by several recent gene
knockout studies in which certain proteins were shown to regulate NF-B
transcriptional activity without affecting its DNA-binding activity. For
example, in mice deficient in the MAP3K NIK, normal NF-
B DNA-binding
activity was observed upon treatment by a variety of cytokines, including TNF,
IL-1 and LTß. However, gene transcription upon LTßR activation was
selectively affected by the absence of NIK
(Yin et al., 2001
).
Therefore, as different TRAFs may recruit a different set of these regulatory
proteins, their biological functions may be modulated by them.
In addition to NF-B and AP-1 activation, TRAF proteins have been
implicated in the crossover to additional signaling pathways. One such example
is TRAF6-mediated activation of Src family kinases. In osteoclasts at least,
TRAF6 plays an indispensable role in the activation of c-Src and subsequently
the anti-apoptotic kinase PKB/Akt (Coffer
et al., 1998
; Wong et al., 1999a). Similarly, TRAF6-dependent
activation of another protein tyrosine kinase Syk has been shown to mediate
IL-1-induced chemokine production (Yamada
et al., 2001
). Therefore, the differential regulation of
NF-
B and AP-1, as well as the specific activation of other signaling
pathways, may collectively contribute to the specific functions of TRAFs.
![]() |
Signaling-dependent TRAF trafficking |
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Although the redistribution of TRAFs into membrane fractions may lead to a
more sustained signaling of the activated receptor, it could also lead to a
depletion of cytoplasmic TRAFs and therefore downregulate subsequent
TRAF-dependent signal transduction (Arch et
al., 2000). Some TRAFs can accumulate in perinuclear compartments
after a particular signaling event (Arch et
al., 2000
; Force et al.,
2000
) but the eventual fate of these TRAFs is not clear. One
possibility is proteasome-dependent TRAF degradation
(Duckett and Thompson, 1997
;
Brown et al., 2001
), which
would limit the recycling of TRAFs for further signal transduction.
Interestingly, several TRAFs have been shown to interact with proteins of the
cytoskeleton and/or of particular membranes. These include the p62
nucleoporin, a component of the nuclear pore central plug
(Gamper et al., 2000
), the
membrane-organizing protein caveolin-1
(Feng et al., 2001
), the
microtubule-binding protein MIP-T3 (Ling
and Goeddel, 2000
) and filamin
(Leonardi et al., 2000
).
Clearly, this is an important field that requires further exploration and may
hold many of the clues to the specificity of TRAF-mediated signal
transduction.
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Perspectives |
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Acknowledgments |
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References |
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