(Journal of Leukocyte Biology. 2002;72:19-23.)
© 2002
by Society for Leukocyte Biology
Mechanisms of TNF receptor-associated factor (TRAF) regulation in B lymphocytes
Gail A. Bishop*,
,
,
Bruce S. Hostager* and
Kevin D. Brown
* Departments of Microbiology,
Internal Medicine, and
Interdisciplinary Immunology Graduate Program, The University of Iowa and Iowa City VAMC, Iowa City
Correspondence: Dr. Gail A. Bishop, Dept. of Microbiology, 3-570 Bowen Science Bldg., The University of Iowa, Iowa City, IA 52242. E-mail: gail-bishop{at}uiowa.edu
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ABSTRACT
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A key component of signaling by members of the tumor necrosis factor receptor (TNF-R) family is interaction with the cytoplasmic adapter proteins known as TRAFs. Several proteins encoded by microbes also interact with TRAFs. A notable example is the CD40 receptor, expressed on antigen presenting cells and providing key activation signals in T cell-dependent B cell activation. CD40 signals to B cells are mimicked by a constitutively active viral protein produced by the Epstein-Barr virus. For each of these receptors, multiple mechanisms of TRAF regulation contribute to signal transduction and the ultimate effect on the B cell. Recent findings concerning these regulatory mechanisms are summarized in this overview.
Key Words: TNF • TNF-R family • EBV • lymphocyte activation • signal transduction
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INTRODUCTION
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All members of the tumor necrosis factor receptor (TNF-R) family of molecules, as well as certain other receptors, use distinct but overlapping sets of cytoplasmic adapter proteins called TRAFs (TNF-R-associated factors) to deliver signals to cells. However, how TRAFs function and how such functions are regulated are not well understood. As the number and variety of receptors using this adapter protein family continue to expand, gaining such an understanding becomes increasingly relevant and important.
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DISCOVERY OF THE TRAF FAMILY
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The first two TRAF proteins (TRAFs 1 and 2) were isolated as proteins associating physically with the cytoplasmic tail of TNF-R2 [1
]. Both share a structural homology in the C-terminus that has since been found in all the known TRAFs, and is hence known as the TRAF domain. In the same year, TRAF3 was identified, also using two-hybrid yeast techniques, and was found not to bind to TNF-R1 or -R2, but to CD40 [2
]. Within several years, TRAFs 4–6 had been isolated [3
4
5
6
7
]. Each member of the TNF-R family has been found to bind a distinct profile of TRAF molecules (reviewed in ref [8
]). With the exception of TRAF1, all TRAF molecules contain a zinc-binding RING finger domain at the N-terminus, and removal of this domain renders the TRAF unable to promote signaling and able to inhibit normal TRAF function as a "dominant negative" (DN) [8
].
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CD40 AND LATENT MEMBRANE PROTEIN 1 (LMP1) IN B CELL ACTIVATION
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CD40 is a member of the TNF-R family expressed constitutively by B lymphocytes, macrophages, and dendritic cells. Upon trimerization by its ligand CD154, expressed on activated T cells, CD40 delivers multiple signals to cells, resulting in a variety of downstream effector functions. These include up-regulation of surface molecules involved in antigen presentation, stimulation of antibody production and isotype switching, secretion of cytokines, and protection from apoptosis (for more extensive recent reviews of CD40 function, see refs [9
10
11
12
13
]). Patients who lack CD40 signaling (because of mutations in the gene encoding CD154) and mice deficient in CD40 or CD154 share a phenotype of susceptibility to recurrent bacterial infections as well as certain intracellular pathogens and show severely impaired production of "switched" immunoglobulin (Ig) isotypes, as well as defects in antigen presentation (reviewed in refs [14
, 15
]). Thus, CD40 signals resulting from cognate interactions between antigen presenting cells and activated T lymphocytes play an integral role in humoral and cell-mediated responses.
Over the past several years, it has become clear that CD40 activation signals to B cells have a potent mimic in the Epstein-Barr virus (EBV)-encoded oncogenic protein, LMP1 (for recent review, see refs. [12
, 16
]). EBV latently infects >90% of the world’s population, and its principal tropism is for the B lymphocyte. LMP1 has been the subject of much scrutiny because it is the only EBV-encoded protein that transforms cultured cells directly, and it is absolutely required for the development of a B cell lymphoma with which reactivation of EBV is associated [16
]. LMP1 contains six membrane-spanning domains in addition to short N-terminal and long C-terminal cytoplasmic domains, and these transmembrane domains can mediate ligand-independent aggregation and signal transduction through the C-terminal cytoplasmic (CY) tail of the molecule [17
, 18
]. LMP1 signals are remarkably similar to those mediated by CD40, including surface molecule up-regulation, IgM and cytokine production, and protection from apoptosis (reviewed in ref [12
]). However, B cell-specific expression of an LMP1 transgene in a CD40-deficient mouse could not restore the T-dependent antibody response completely [19
]. This failure may in part be a result of lack of expression of the transgene in macrophage or dendritic cell populations, where CD40 is normally also expressed and shown to play important roles. However, it is also likely that the CY domains of CD40 and LMP1, which are quite different in sequence, are not equivalent in the signals they deliver to the B cell. Recently, study of B cell clones expressing wild-type (Wt) CD40 or a CD40-LMP1 hybrid molecule at similar levels revealed that LMP1 delivers signals that are amplified and sustained when compared with CD40 signals [20
]. Signaling via both receptors uses TRAF molecules, and evidence is accumulating that their use and regulation play important roles in the nature of the signals delivered.
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ASSOCIATION OF TRAFs WITH CD40 AND LMP1
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Between 1994 and 1996, as described above, the six currently characterized TRAF proteins were isolated. During this time, the exciting finding was also made that LMP1 binds to proteins with homology to TRAF molecules [21
]. In this initial study, it was found that LMP1 can bind two CY proteins now known to be TRAF1 and TRAF3. Subsequently, it was determined that LMP1 can also interact with TRAF2 [22
, 23
], although unlike CD40, which shows robust binding to TRAF2 [24
], TRAF2-LMP1 binding is much weaker than LMP1 association with TRAFs 1 and 3 [25
]. Other differences in TRAF binding also exist between the two receptors. Isolation of TRAF5 was demonstrated in 1996 by two papers appearing in the same month; one reporting group found, by yeast two-hybrid analysis, that TRAF5 associates with CD40 [4
], while a second group, using the same technique, saw TRAF5 association with the lymphotoxin ß receptor, but not with CD40 [5
]. Subsequent binding studies using purified CD40 and TRAF peptides also suggested that TRAF5 does not interact directly with CD40, but might do so via heterodimerization with TRAF3 [26
]. We should emphasize, however, that none of these studies has examined the binding of endogenous CD40 to endogenous TRAF5 in B lymphocytes. When we examined TRAF association with CD40 in B cells, although B cell TRAF5 can be detected easily, we find no evidence of association, either direct or indirect, with CD40 (K.D.B. and G.A.B., unpublished results). Because our binding procedures routinely detect the very weak binding of LMP1 to TRAF2 [20
, 27
], this suggests that the CD40-TRAF5 association does not occur in B cells or is extremely weak. TRAF5-deficient mice do show certain defects in CD40-mediated functions, but these differences from Wt are rather modest and may be caused by developmental changes in the mice [28
]. In contrast, TRAF5 has been shown to associate directly with LMP1 [29
], and we have verified that association of LMP1 with endogenous TRAF5 also occurs in B cells (unpublished results).
Another difference seen between the TRAF binding properties of CD40 and LMP1 is the nature of the association with TRAF1. LMP1 is able to bind directly to TRAF1 [23
, 25
]. While peptide binding studies suggest that direct TRAF1-CD40 binding is also possible, there is no evidence that CD40 binds TRAF1 directly in B cells, although it can clearly do so by heterodimerization with TRAF2. We recently have found that mutant CD40 molecules unable to bind TRAF2 are also unable to associate with TRAF1 (B.S.H. and G.A.B., unpublished results), further reinforcing the need for TRAF1 to heterodimerize with TRAF2 for CD40 binding.
While TRAF5 clearly associates with LMP1 but may not bind CD40, the converse appears to be true for TRAF6. Although the CD40:TRAF6 association is weaker than CD40 binding to TRAFs 2 and 3 [24
, 26
], this binding can be detected readily between endogenous proteins in B cells [30
]. In contrast, although several recent studies implicate TRAF6 as playing a role in the LMP1 signal cascade [29
, 31
], no published data have yet shown that endogenous TRAF6 binds directly or indirectly to LMP1 expressed in B cells, and our own unpublished experiments also fail to find this association. It has been suggested that TRAF6 may influence LMP1 signaling by acting through a distinct receptor [29
]; this appears a likely possibility. In Table 1
, we summarize TRAF binding to CD40 and LMP1 in B cells. Because the above information illustrates the pitfalls of drawing conclusions about protein-protein binding in artificial systems, we have only listed interactions verified to occur between TRAFs and receptors expressed at normal levels in B lymphocytes. It is clear that there are a number of differences in the individual TRAFs bound, as well as the manner (direct vs. indirect) and strength of TRAF binding, between CD40 and LMP1. Such differences, summarized in Table 1
, may make important contributions to differences in signaling between the two receptors.
The aforementioned possibility that TRAF6 may regulate LMP1 signaling without associating directly with its receptor complex illustrates the important point that TRAFs may play significant roles in signaling by a particular receptor without direct association. This can be accomplished by influencing signaling through additional TRAF-binding receptors that participate in the signaling cascade. An example of this situation has been found recently in regards to the role of TRAF2 in CD40-mediated IgM secretion. Although TRAF2 binds CD40 directly and is clearly important for certain CD40-mediated functions [32
, 33
], mutant CD40 molecules that cannot bind TRAF2 induce normal levels of B cell IgM production [32
]. However, it was subsequently found that truncated DNTRAF2 inhibits this function, independent of binding to CD40 [34
]. This interesting result led us to hypothesize that the effect of DNTRAF2 is the result of inhibition of an additional TRAF2-binding receptor that contributes to CD40-mediated IgM secretion. Recent findings have confirmed that the receptor in question is TNF-R2 [35
]. It had been shown previously that CD40 can induce B cell TNF production and that TNF can induce IgM secretion [36
, 37
]. We found that blocking antibodies to TNF or TNF-R2 inhibits CD40-mediated IgM production and that inhibition of this function by induced expression of DNTRAF2 is redundant with addition of saturating amounts of blocking antibodies (Abs) [35
]. Further, a B cell line engineered to be completely deficient in TRAF2 shows a reduced ability to secrete IgM in response to CD40, and the ability to respond to TNF is abrogated completely. However, both are fully restored by inducible expression of transfected TRAF2 (Fig. 1
). Thus, CD40 and LMP1 can use TRAFs for signaling in direct and indirect ways.
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Figure 1. TRAF2 influence on CD40-mediated IgM production via TNFR2. A TRAF2-/- subclone of the mouse B cell line CH12.LX (CH12.T2-/-; unpublished results) was stably transfected with inducible Wt mouse TRAF2, using an isopropylthiogalactoside (IPTG)-inducible system described previously [34
]. Cells were incubated in the absence or presence of the inducer IPTG for 18 h before addition of recombinant mouse TNF (50 pg/ml) or agonistic anti-CD40 monoclonal Ab (2 µg/ml). Cells were incubated for an additional 48 h before harvest and enumeration of IgM-secreting cells/106 viable recovered cells by hemolytic plaque assay as described [32
]. Pfc, Plaque-forming cells (IgM-secreting cells). BCM, B cell medium. Results are mean ± SE of replicate samples and are representative of three similar experiments.
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MEMBRANE RAFTS IN CD40 AND LMP1 SIGNALING
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In recent years, it has become clear that cholesterol and glycosphingolipid-enriched microdomains in the plasma membrane (membrane rafts) serve as sites for assembly of a variety of receptor signaling complexes (reviewed in refs [38
, 39
]). In B cells, LMP1 is localized constitutively to rafts, and CD40 redistributes to this compartment following engagement; both receptors recruit TRAFs 2 and 3 to membrane rafts [40
, 41
].
It is interesting that the Zn-binding RING domains of TRAFs 2 and 3 are involved in optimal raft recruitment, as their removal or incubation with a Zn-chelating agent inhibits CD40-mediated raft recruitment, and the same agent blocks CD40-mediated c-jun kinase (JNK) activation [41
]. This suggests that TRAF RING domains interact with as yet unidentified raft-localized proteins.
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TRAF REGULATION IN CD40 AND LMP1-MEDIATED SIGNALING
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CD40 serves as a normal, critical, B-cell activation receptor, while LMP1 is an oncogenic protein for B cells. What molecular differences between their signaling pathways underlie this important functional difference? Although initiation of signaling is constitutive for LMP1 versus ligand induced for CD40, our earlier studies using ligand-induced signaling through hybrid receptors with the LMP1 CY domain suggested that this alone cannot explain the differences in functional outcome between CD40 and LMP1 signaling [18
]. To compare signals delivered by LMP1 and CD40 directly, we reasoned that we must devise a model system in which the same stimulus is used to initiate signaling by each molecule, and each is expressed at similar levels on the cell membrane. To this end, we produced B cell subclones stably and inducibly expressing LMP1, an LMP1 hybrid molecule with the CY domain of CD40, Wt CD40, or a hybrid molecule with the CY domain of LMP1. Cells expressing molecules with the LMP1 membrane-spanning domains are stimulated by induction of expression of these self-aggregating molecules; those expressing receptors with the external and transmembrane domains of CD40 initiate signaling when engaged by CD154 or anti-CD40 Abs. Using these models, we discovered that LMP1 delivers activation signals to B cells that are initiated more quickly, are amplified, and can be sustained for longer than those delivered by CD40 [20
]. This is true for B cell effector functions (surface molecule up-regulation, IgM secretion, cytokine production) as well as activation of nuclear factor 
-B and JNK. Because amplification is seen in such an early event as JNK activation, this suggests that early signaling events differ between CD40 and LMP1. This may in part be a result of differential composition of TRAFs in the signaling complex, as shown in Table 1
and suggested by a recent study [42
]. However, the difference is also associated with a very different outcome for TRAFs 2 and 3 regulation by the two receptors. It was found that shortly (within 10 min) after their raft recruitment, TRAF 2 and 3 begin to undergo CD40-dependent degradation [20
]. However, association with LMP1 does not initiate this degradation, although LMP1 cannot block CD40-induced degradation in the same B cell [20
]. Several lines of evidence now indicate that the RING domain of TRAF2 initiates the process, which involves TRAF ubiquitination and proteasome-dependent degradation [20
]. Removal of the TRAF2 RING domain or simply mutation of a single cysteine critical to its structure (C34) eliminates CD40-mediated modification and degradation [44
]. Additionally, CD40 cannot initiate degradation of TRAFs in a cell line containing a temperature-sensitive mutant E1 ubiquitin ligase, when at the nonpermissive temperature [44
]. Finally, inhibition of the activity of the 26S proteasome blocks TRAF degradation [20
] and potentiates CD40 signaling to B cells, so that it now more closely resembles LMP1-induced signaling [44
]. Taken together, these studies strongly suggest that receptor-induced degradation of TRAFs 2 and 3 serves as an important feedback regulatory mechanism that limits the amount and duration of activation signals. A schematic illustration of these differences in TRAF regulation is shown in Figure 2
.
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Figure 2. TRAF regulation by CD40 and LMP1. CD40 is shown on the left; LMP1 is on the right. TRAFs are indicated as associated molecules containing receptor-binding and Zn-binding domains with the exception of TRAF1, which lacks the Zn-binding region. Ligation of CD40 by CD154 results in its recruitment into membrane lipid rafts to which it recruits TRAF molecules with which it associates (see Table 1
). Self-aggregation of the transmembrane domains of clustered LMP1 molecules mediates ligand-independent raft localization and TRAF recruitment. Subsequent to their induced association with CD40, TRAFs 2 and 3 are degraded, which will also result in release of CD40-associated TRAF1 to the cytoplasm. TRAF6 association requires greater CD40 cross-linking [43
], and its recruitment to rafts is slower than TRAFs 2 and 3 [41
]; thus, degradation of TRAFs 2 and 3 may promote enhanced TRAF6-CD40 association. Boxes with question marks indicate that CD40 and TRAFs are likely to interact with not-yet-defined raft-localized proteins to initiate signaling cascades. In contrast to CD40, association of TRAFs with LMP1 in rafts does not promote TRAF degradation, permitting amplified and sustained signaling [20
]. The most C-terminal signaling region of LMP1 is known to be important to LMP1 signaling and may interact cooperatively with the more membrane-proximal TRAF-binding region, but endogenously expressed B cell proteins that bind to this region remain to be characterized [27
].
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CONCLUSIONS
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TRAFs constitute a growing family of cytoplasmic adapter proteins that interact with a large number and variety of signaling receptors. Members of the family clearly have distinct functions as well as sharing certain common modes of action. A more detailed understanding of how TRAFs interact with receptors and the molecular details of how they trigger and influence signaling pathways will disclose understanding of signaling by a large group of receptors, those contributing to normal cellular activation and death as well as proteins encoded by microbial pathogens.
Received November 25, 2001;
revised January 30, 2002;
accepted January 31, 2002.
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S. Wu, P. Xie, K. Welsh, C. Li, C.-Z. Ni, X. Zhu, J. C. Reed, A. C. Satterthwait, G. A. Bishop, and K. R. Ely
LMP1 Protein from the Epstein-Barr Virus Is a Structural CD40 Decoy in B Lymphocytes for Binding to TRAF3
J. Biol. Chem.,
September 30, 2005;
280(39):
33620 - 33626.
[Abstract]
[Full Text]
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M. E. Munroe and G. A. Bishop
Role of Tumor Necrosis Factor (TNF) Receptor-associated Factor 2 (TRAF2) in Distinct and Overlapping CD40 and TNF Receptor 2/CD120b-mediated B Lymphocyte Activation
J. Biol. Chem.,
December 17, 2004;
279(51):
53222 - 53231.
[Abstract]
[Full Text]
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P. Xie and G. A. Bishop
Roles of TNF Receptor-Associated Factor 3 in Signaling to B Lymphocytes by Carboxyl-Terminal Activating Regions 1 and 2 of the EBV-Encoded Oncoprotein Latent Membrane Protein 1
J. Immunol.,
November 1, 2004;
173(9):
5546 - 5555.
[Abstract]
[Full Text]
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P. Xie, B. S. Hostager, and G. A. Bishop
Requirement for TRAF3 in Signaling by LMP1 But Not CD40 in B Lymphocytes
J. Exp. Med.,
March 1, 2004;
199(5):
661 - 671.
[Abstract]
[Full Text]
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TOP
ABSTRACT
INTRODUCTION
