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1 October 2001, Volume 20, Number 44, Pages 6482-6491
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Tumor necrosis factor receptor-associated factors (TRAFs)
John R Bradley1 and Jordan S Pober2

1Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK

2Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

Correspondence to: J R Bradley, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: john.bradley@addenbrookes.nhs.uk

Abstract

Tumor necrosis factor receptor-associated factors (TRAFS) were initially discovered as adaptor proteins that couple the tumor necrosis factor receptor family to signaling pathways. More recently they have also been shown to be signal transducers of Toll/interleukin-1 family members. Six members of the TRAF family have been identified. All TRAF proteins share a C-terminal homology region termed the TRAF domain that is capable of binding to the cytoplasmic domain of receptors, and to other TRAF proteins. In addition, TRAFs 2-6 have RING and zinc finger motifs that are important for signaling downstream events. TRAF proteins are thought to be important regulators of cell death and cellular responses to stress, and TRAF2, TRAF5 and TRAF6 have been demonstrated to mediate activation of NF-kappaB and JNK. TRAF proteins are expressed in normal and diseased tissue in a regulated fashion, suggesting that they play an important role in physiological and pathological processes. Oncogene (2001) 20, 6482-6491.

Keywords

tumor necrosis factor (TNF); TRAF; interleukin-1; receptor; signaling

Tumor necrosis factor receptor-associated factors (TRAFs) are a family of adaptor proteins that share a common structural domain at their C-terminus. This conserved region allows TRAFs to interact with cell surface receptors or other signaling molecules. Although initially identified through their interaction with tumor necrosis factor receptor-2 (TNFR2), TRAFs are able to serve as adaptor proteins for a wide variety of receptors that are involved in regulating cell death and survival and cellular responses to stress.

TRAF1 was identified as a novel 45 kd protein that could be co-immunoprecipitated with human TNF receptor 2 (TNFR2) transfected into the murine interleukin-2-dependent cytotoxic T cell line CT6, and also from CT6 cell lysates by a GST fusion protein containing the region of human TNFR2 required for signal transduction (Rothe et al., 1994). At the same time TRAF2 was identified as a novel 56 kd protein by using the yeast two-hybrid system to detect proteins that interact directly with the cytoplasmic domain of hTNFR2. Despite the co-immunoprecipitation studies, only a very weak interaction between TRAF1 and the cytoplasmic domains of hTNFR2 or mTNFR2 could be detected using the two-hybrid system. This seeming contradiction was reconciled by the observations that a strong heteromeric interaction occurred between TRAF1 and TRAF2, and that TRAF1 and TRAF2 could form homo- and heterotypic dimers. Consequently, TRAF1 and TRAF2 can associate with the cytoplasmic domain of TNFR2 as a heterodimeric complex in which only TRAF2 contacts the receptor directly.

The two proteins were found to share 53% homology in their C-terminal domains, providing evidence of a novel structural domain of about 150 amino acids that was designated the TRAF domain. TRAF domains can be subdivided into TRAF-N and TRAF-C subdomains, corresponding to the amino- and carboxy-terminal proteins of the common TRAF sequence. At their less conserved N-terminal regions TRAF1 and TRAF2 were found to be free of proline and glycine residues which destabilize alpha-helices, exhibiting a distribution of polar and non polar amino acids which could favor formation of coiled-coil alpha-helices. At its N-terminus TRAF2 contains a RING finger sequence motif, and five zinc finger motifs. RING fingers have a characteristic pattern of cysteines and histidines that are capable of forming zinc finger structures, which are thought to mediate DNA binding and protein-protein interactions. RING fingers also can serve at ubiquitin ligases, targeting proteins for degradation by the proteosome (Lorick et al., 1999). TRAF1 contains zinc fingers but lacks the RING finger domain found in TRAF2.

Rothe and colleagues proposed that TRAF1 and TRAF2 were members of a novel family of signal transducers that could interact with TNFR2, and perhaps other members of the TNF receptor superfamily. This hypothesis proved well founded. To date six members of the TRAF family which share the conserved C-terminal domain have been identified.

TRAF3 was identified using the yeast two hybrid system as a CD40 binding protein (Hu et al., 1994), also termed CAP-1 (CD40 associated protein-1) (Sato et al., 1995) and CRAF1 (Cheng et al., 1995), and as a protein that interacts with the Epstein-Barr virus transforming protein LMP1 (Mosialos et al., 1995). TRAF4 was identified by differential screening of a cDNA library of breast cancer-derived metastatic lymph nodes. It was originally termed CART1, because it contained a conserved C-rich domain associated with RING and TRAF (CART) domains (Régnier et al., 1995). TRAF5 was identified as a lymphotoxin-beta receptor interacting protein by polymerase chain reaction amplification using degenerate oligonucleotide primers corresponding to conserved amino acids in the TRAF domain of TRAF1, TRAF2, and TRAF3 (Nakano et al., 1996), and independently as a CD40 binding protein using the yeast two hybrid system (Ishida et al., 1996). TRAF 6 was separately identified as a signal transducer involved in the activation of NF-kappaB by CD40 (Ishida et al., 1996) and interleukin 1 (Cao et al., 1996), using the yeast two hybrid system and screening of an EST expression library respectively. Like TRAF2, TRAFs 3-6 have an N-terminal RING finger as well as zinc finger motifs.

Before considering the structure and potential functions of each of these TRAF proteins further, we will first describe the two main receptor families with which they have been shown to interact.

TNF receptor family

Tumor necrosis factor (also known as TNF-alpha), and TNF-beta (also known as lymphotoxin) are structurally related molecules that modulate a wide spectrum of responses, including the activation of many genes involved in inflammatory and immuno-regulatory responses, cell proliferation, anti-viral responses, growth inhibition and cell killing. TNF and lymphotoxin compete for binding to two cell surface receptors, TNFR1 (CD120a, 55 kd) and TNF-R2 (CD120b, 75 kd). TNFR1 and TNFR2 both contain a 6-cysteine consensus motif repeated four times in their extracellular regions, but have shown no similarity in their cytoplasmic regions. Since the identification of these two distinct TNF receptors a growing number of TNF receptor family members have been identified through homologies in their extracellular domains, which contain cysteine residues arranged in a repetitive pattern (Table 1). These cysteine rich domains form tertiary structures that are responsible for ligand binding, and most of the identified ligands are structurally homologous to TNF. X-ray crystallography has shown that lymphotoxin binds as a trimer to trimeric TNFR1 (Banner et al., 1993), and it has been predicted that most ligands bind to TNF receptor family members as trimeric receptor-ligand complexes. A number of viral proteins containing cysteine-rich repeats have also been identified. These viral TNF receptor homologues are thought to suppress the host immune response by sequestering TNF (McFadden et al., 1997). The entry of herpes simplex virus-1 into cells is mediated by a member of the TNF receptor family (Montgomery et al., 1996).

Although members of the TNF receptor superfamily signal a wide range of overlapping cellular responses, including differentiation, proliferation, NF-kappaB activation, stress-activated protein kinase (SAP kinase), especially Jun N-terminal kinase (JNK) activation, and cell death, their cytoplasmic domains are devoid of intrinsic enzymatic activity, and generally lack recognizable common motifs. The exception occurs in a subgroup, which contain a protein motif of approximately 80 amino acids called a 'death domain', which is able to bind other death domain containing proteins. Death domains were originally identified as regions in the cytoplasmic tails of TNFR1 and the death inducing receptor Fas/Apo1 (CD95), which were required for the induction of apoptosis. Four death domain containing adaptor proteins couple TNFR1 and Fas to signaling pathways. FADD (Fas-associated death domain protein, also known as MORT1 or mediator of receptor-induced cytotoxicity 1) (Chinnaiyan et al., 1995; Boldin et al., 1995), TRADD (TNF receptor-associated death domain protein) (Hsu et al., 1995), RIP (receptor interacting protein) (Stanger et al., 1995), and RAIDD (receptor-interacting protein (RIP)-associated ICH-1/CED-3-homologous protein with a death domain)/CRADD (caspase and RIP adaptor with death domain) (Duan and Dixit, 1997; Ahmad et al., 1997) all contain death domains and bind through homo- and hetero-typic interactions to the receptors and to each other. Induction of apoptosis by these adaptor proteins involves caspases, a family of ICE-related (interleukin-1 beta-converting enzyme) aspartyl-directed cysteine proteases that exist in cells as inactive precursors that become activated by cleavage at an internal caspase substrate site, so that caspases are typically activated as a result of cleavage by themselves or other caspases. Caspases have been found to be activated following direct association with death domain proteins. Caspase-8 (FLICE) and caspase-10 (FLICE2) bind through N-terminal death effector domains (DED) to an N-terminal DED in FADD (Muzio et al., 1996) and caspase-2 binds through an N-terminal motif termed CARD (caspase recruitment domain) to a CARD in RAIDD (Chou et al., 1998).

TRADD has not been shown to interact directly with caspases, and yet was identified as a novel 34 kDa protein that specifically interacts with an intracellular domain of TNFR1 known to be essential for mediating programmed cell death (Hsu et al., 1995). Furthermore, these studies showed that TRADD leads to both apoptosis and activation of NF-kappaB, and that the C-terminal 118 amino acids of TRADD are sufficient to trigger both of these activities and likewise sufficient for interaction with the death domain of TNFR1. This capacity for TRADD to initiate two divergent signaling cascades was explained by the observation that TRADD can directly interact with FADD, leading to induction of apoptosis, and also with TRAF2 leading to activation of NF-kappaB and JNK (Hsu et al., 1996). Thus, two mechanisms for TRAF proteins to interact with members of the TNF receptor superfamily were defined. TRAF2 can interact directly with the cytoplasmic tail of receptors such as TNFR-2 that do not contain death domains, and indirectly with death domain containing receptors through association with their death domain adaptor proteins.

Toll/IL-1 receptor family

Interleukin-1 (IL-1) signals its pro-inflammatory effects through the type-1 IL-1 receptor (IL-1R1). The signaling pathways involve recruitment to the cytoplasmic tail of the receptor of the death domain containing adaptor protein MyD88. The recruitment of the receptor associated kinases, IRAK (IL-1 receptor-associated kinase) (Cao et al., 1996) and/or IRAK-2 (Muzio et al., 1997) is then required for activation of NF-kappaB and SAP kinases. TRAF6 was identified as a TRAF family member that could activate NF-kappaB when overexpressed in human embryonic kidney 293 cells, and a dominant negative mutant of TRAF6 was found to inhibit NF-kappaB activation signaled by IL-1, but not TNF (Cao et al., 1996). TRAF6 participates in IL-1 signaling by associating with IRAK and IRAK-2, coupling the receptor complex to downstream kinases (Muzio et al., 1998). Although TRAF6 can associate with IRAK and IRAK can associate with the IL-1R complex, the IRAK-TRAF6 complex has not been shown to associate with the IL-1 receptor, suggesting that IRAK may dissociate from the receptor before binding to TRAF6 (Ling and Goeddel, 2000).

IL-1R-1 has a cytoplasmic domain of approximately 200 amino acids with sequence similarity to the Drosophila Toll receptor. Toll was first described as a protein important in establishing dorso-ventral polarity in Drosophila, but is also important for defense against fungal infection in the adult fly (Lemaitre et al., 1996). The homologous cytosolic Toll/interleukin-1 receptor (TIR) domain has defined a Toll/interleukin-1 receptor (TIR) family of mammalian, insect, plant and viral proteins. Family members include the IL-18 receptor (Torigoe et al., 1997), the Th2 cell regulator T1/ST2 (Coyle et al., 1999), and a number of human Toll-like receptors (TLRs). TLR-4 is required for responsiveness to LPS (Hirschfeld et al., 2000). A dominant negative mutant of TRAF6 inhibits NF-kappaB activation through hToll, and it is likely that TRAF6 acts as a signal transducer for other members of the Toll/IL-1R family (Muzio et al., 1998).

Each member of the TRAF family was identified through its interaction with one or more members of the TNF receptor family or IRAK signaling molecules. The interactions and functions of individual TRAF proteins have often been considered predominantly in relation to the first receptor with which it was found to interact. However, it is clear that TRAF proteins form a complex network in which each TRAF is able to interact with, and influence the function of, many signaling molecules, either directly or through interaction between different TRAF family members. With this background, we will now consider each of the TRAF proteins in more detail.

TRAF1

The absence of an N-terminal ring finger, and the fact that its zinc fingers are not arranged in CART (C-rich associated with RING and TRAF) domains make TRAF1 unique amongst the TRAF family. In addition TRAF1 is inducible and shows a restricted tissue distribution. TRAF1 has been shown to interact indirectly with TNFR2, and directly with several TNFR family members, including CD30 (Lee et al., 1996; Gedrich et al., 1996), 41-BB (Arch and Thompson, 1998), herpes virus entry mediator (Marsters et al., 1997), RANK (receptor activator of NF-kappaB, also known as TNF-related activation-induced cytokine receptor, TRANCE-R) (Wong et al., 1998; Galibert et al., 1998), CD40 (Pullen et al., 1999), AITR (activation-inducible TNFR family member) (Kwon et al., 1999), the Epstein-Barr virus transforming protein LMP-1 (Latent membrane protein-1) (Kaye et al., 1996) and BCMA (B cell maturation protein) (Hatzoglou et al., 2000). In addition TRAF1 has been shown to associate with a number of cytoplasmic proteins including TANK/I-TRAF (TRAF-associated NF-kappaB activator/TRAF interacting protein) (Cheng and Baltimore, 1996; Rothe et al., 1996), TRIP (TRAF-interacting protein) (Lee et al., 1997), A20 (Song et al., 1996), RIP (Hsu et al., 1996), RIP2/CARDIAK (CARD-containing interleukin (IL)-1 beta converting enzyme (ICE) associated kinase) (Thome et al., 1998), and the caspase 8 binding protein FLIP (FLICE inhibitory protein) (Chaudhary et al., 1999). Although most of these molecules have been implicated in NF-kappaB activation, as well as JNK activation and apoptosis, the role of TRAF1 in these processes is not fully understood.

TRAF1 has little or no effect on ligand independent NF-kappaB or JNK when overexpressed (Schwenzer et al., 1999; Leo et al., 1999), but appears to regulate transcriptional activation induced by other mediators. Overexpression of full-length TRAF1 has been reported to suppress activation of NF-kappaB by TNF, IL-1, TRAF2 and TRAF6 in human embryonic kidney cells (Carpentier and Beyaert, 1999). In HELA cells full-length TRAF1 potentiates TNF or IL-1 induced NF-kappaB activation, and prolongs TNF induced JNK activation, whereas overexpression of an N-terminal deletion mutant of TRAF1 interferes with TNF induced activation of NF-kappaB and JNK (Schwenzer et al., 1999). TRAF1 may act as a co-stimulator of NF-kappaB by CD30 and LMP-1 (Régnier et al., 1995; Devergne et al., 1996; Duckett et al., 1997). To date, there have been no reports of mice with natural or targeted disruption of the TRAF1 gene.

An explanation for these apparently divergent roles of TRAF1 may in part be provided by the observation that TRAF1, but not other members of the TRAF family, is a substrate for caspases that are activated by TNF family death receptors (Leo et al., 2001; Jang et al., 2001). TRAF1 is cleaved at a 160LVED163 motif to yield two fragments of approximately 28 and 22 kd. The larger C-terminal TRAF domain containing fragment can bind TRAF2, sequestering it from the TNFR1 complex (Jang et al., 2001). Overexpression of this C-terminal TRAF1 fragment is capable of suppressing NF-kappaB induction by TNFR1 and TRAF2, and enhancing the apoptotic signal induced through this receptor, consistent with the observation that inhibition of TNFR1 mediated NF-kappaB activation can enhance the apoptotic signal transduced through this receptor (Beg and Baltimore, 1996; Wang et al., 1996; Van Antwerp et al., 1996; Liu et al., 1996). In contrast, the N-terminal fragment, or a non-cleavable TRAF1 protein in which Asp163 was mutated to alanine, had no significant effect on TNFR1 or TRAF2 mediated NF-kappaB activation. Thus cellular responses to signaling through TNF family death receptors may depend on the relative amounts of full-length versus caspase cleaved TRAF1. Interestingly, TRAF1 is upregulated by ligands of the TNF family, and its promoter contains several functionally important NF-kappaB binding sites (Schwenzer et al., 1999).

TRAF2

Structural studies of TRAF2

TRAF2 has been the most extensively studied TRAF, both in terms of structure and function. Mutational analysis of TRAF2 has shown that distinct domains are involved in interaction with other proteins and signaling functions (Takeuchi et al., 1996). The two distinct TRAF-N and TRAF-C subdomains of the TRAF domain appear to independently mediate self-association and interaction with TRAF1. Interaction with TNFR2 and TRADD requires sequences at the C terminus of the TRAF-C domain, whereas interaction with RIP occurs via sequences at the N-terminus of the TRAF-C domain. The N-terminal RING finger, and two adjacent zinc fingers are required for NF-kappaB activation. Crystallographic studies of the TRAF domain (Park et al., 1999) have shown that the TRAF-N domain contains a coiled-coil domain that forms a single alpha-helix. The TRAF-C domain forms a novel eight-stranded anti-parallel beta-sandwich. The TRAF domain self associates into a trimer in the shape of a mushroom, with the TRAF-C domain as the cap, and the coiled-coil domain as the stalk. The amino acid residues contributing to trimerization of the TRAF domain of TRAF2 are conserved among the TRAF-family members. In crystal structure a receptor peptide from TNFR2 binds to a shallow surface depression on the side of the mushroom-shaped trimer. The peptide contacts only one TRAF domain, with no contact to the other two molecules of the trimer. An SXXE motif, where X may be one of many amino acids, in the TNFR2 peptide interacts with three residues in TRAF2 (R393, Y395 and S467) that are conserved in TRAFs 1, 2, 3 and 5. In TRAF6 only R393 is conserved, whereas in TRAF4, which has not yet been shown to interact with any receptors, none of these residues are conserved. Other linear sequences mediate interaction between TRAFs and other receptors. For example, a PXQX(T/S) TRAF binding site has been identified in CD27 (Akiba et al., 1998); CD30 (Gedrich et al., 1996; Aizawa et al., 1997; Boucher et al., 1997), CD40 (Lee et al., 1999), and LMP-1 (Brodeur et al., 1997; Sandberg et al., 1997).

Although signaling by TRAF molecules involves the N-terminal RING and zinc finger motifs, the structural basis for downstream events of TRAF2-mediated signal transduction are largely unknown. The TRAF domain of TRAF2 binds receptor peptide without significant conformational change, although full-length TRAF proteins may behave in a different manner. However the downstream events of TRAF2 mediated signal transduction, particularly with reference to activation of the NF-kappaB and activating protein-1 (AP-1) families of transcription factors, have been extensively characterized.

Role of TRAF2 in NF-kappaB activation

NF-kappaB is comprised of dimers of c-Rel, RelA, RelB, p50, or p52 that are endogenously complexed to members of the IkappaB family of inhibitor proteins, which sequester NF-kappaB silently in the cytoplasm. Signals that lead to the degradation of IkappaB permit nuclear translocation of NF-kappaB, where it activates transcription of many genes with NF-kappaB binding sites. At least two different kinases, NF-kappaB-inducing kinase (NIK) and mitogen activated protein kinase/extracellular signal-regulated kinase (ERK) kinase-1 (MEKK1) can phosphorylate IkappaB kinases (IKKs), which in turn phosphorylate IkappaB. Although intimal biochemical experiments suggested that TRAF2 mediates NF-kappaB activation through interaction with NF-kappaB-inducing kinase (NIK), mice with targeted disruptions of the NIK gene are deficient in NF-kappaB activation in response to signals from the LT-beta receptor (Luftig et al., 2001), a TRAF3 or TRAF5 pathway, yet retain TNFR1 signals involving TRAF2. Nevertheless, the TRAF2 interaction with NIK may still be a useful model for understanding interactions with other kinases. A WKI motif within the TRAF domain of TRAF2, that is conserved among TRAF family members, is required for NIK binding and NF-kappaB induction. NIK itself contains a TRAF binding domain, and is able to interact with TRAF2 (and also TRAF1, 3, 5, and 6; Song et al., 1997). The TRAF binding domain contains within it an IKK interacting domain. A mutation within the IKK binding domain that interferes with IKKalpha binding but not binding of TRAF1, 2, 3 or 6 to NIK and blocks NF-kappaB activation has been described (Luftig et al., 2001).

Three new TRAF-domain containing human proteins termed TEFs (TRAF domain-encompassing factors) have recently been identified using bioinformatics approaches. One of these proteins, USP7 (TEF1), is a ubiquitin-specific protease, in which the TRAF domain is located in the N-terminal part of the molecule, rather than the C-terminal localization seen in classical TRAF family members. Recruitment of USP7 to TRAFs might be expected to interfere with NF-kappaB activation by preventing I-kappaB degradation resulting from polyubiquination. In support of this USP7 inhibits NF-kappaB induction caused by transient over-expression of TRAF2 and/or TRAF6 (Zapata et al., 2001). However, expression of a TRAF domain-containing region of USP7 in the absence of its ubiquitin-protease domain is more inhibitory than full-length USP7.

Several other molecules that influence TRAF2 mediated NF-kappaB activation have been described. TRIP (TRAF-interacting protein) inhibits TRAF2 mediated NF-kappaB activation (Lee et al., 1997), whereas I-TRAF/TANK has been described as both an inhibitor (Rothe et al., 1996) and a co-inducer of TRAF2 mediated NFkappaB activation (Cheng and Baltimore, 1996). Receptor interacting protein-2 (RIP2) was identified as a novel NF-kappaB-activating and cell death inducing kinase that can be recruited to the TNFR1 and CD40 receptor signaling complexes. RIP2 interacts directly with TRAF1, TRAF5, and TRAF6, but not with TRAF2, TRAF3 or TRAF4 (McCarthy et al., 1998). Although RIP2 and TRAF2 do not directly interact, a dominant negative TRAF2 can inhibit RIP2-induced NF-kappaB activity, suggesting that TRAF2 may interact with RIP2 through TRAF1. The zinc finger protein A20 can also act as an inhibitor of NF-kappaB activation through interaction with TRAF1/TRAF2 (Song et al., 1996).

Role of TRAF2 in regulation of AP-1

AP-1 is a member of the basic region leucine zipper family of transcriptional activators and is usually formed from a homo- or heterodimer of Jun, Fos, and activating transcription factor (ATF) family members (Karin et al., 1997). TNF activates two subfamilies of the mitogen-activated protein kinase (MAPK) family of serine/threonine kinases that together are largely responsible for the regulation of AP-1. These are the Jun NH2-terminal kinases (JNKs), also known as stress activated protein kinase 1 (SAPK1) and the p38 kinases (also known as SAPK2). Activation of these kinases involves a protein kinase cascade in which JNK or p38 are activated by a MAPK kinase (MAPKK), also known as SAPK/ERK kinase (SEK) or MEK (MAPK/ERK kinase), which is itself phosphorylated by a MAPKK kinase (MAPKKK, also known as MEKK), which can be activated by phosphorylation by germinal center kinase (GCK, a MAPKKK kinase) and germinal center kinase-related kinase (GCKK). TRAF2 can interact with the SAPK activators MEKK1 (Baud et al., 1999), apoptosis signal-regulating kinase-1, also known as Ask1, a MAPKKK (Nishitoh et al., 1998; Hoeflich et al., 1999), germinal center kinase (Yuasa et al., 1998) and the germinal center kinase-related kinase (Shi and Kehrl, 1997; Shi et al., 1999). Ligand induced oligomerization of chimeric TRAF2 proteins in which the amino-terminal is fused to an FK506 binding immunophilin is sufficient to induce MEKK1 binding and JNK activation (Baud et al., 1999).

TRAF2 is thus able to regulate two distinct kinase cascades which lead to activation of NF-kappaB and JNK. Evidence that TRAF2 mediated NF-kappaB activation can be disengaged from JNK activation is provided by studies using the rotavirus caspid protein V4 and its cleavage product VP8*, which contains the conserved TRAF interacting sequence PXQXT, and can selectively direct transcription through NF-kappaB via a TRAF2-NIK signaling pathway whilst inhibiting transcriptional responses through AP-1 (LaMonica et al., 2001).

Genetic manipulation of TRAF2

Further clarification of the distinct roles of TRAF2 in NF-kappaB and JNK activation is provided by experiments using dominant negative TRAF2 molecules and TRAF2 null mice. In vitro studies have shown that expression of a dominant negative TRAF2 mutant lacking the amino-terminal RING finger domain (TRAF2DN) prevents TNF-induced, but not IL-1-induced, IkappaBalpha degradation and NF-kappaB activation, and also TNF induced JNK activation (Rothe et al., 1995; Jobin et al., 1999). However, mice expressing this dominant negative TRAF2 transgene show normal TNF-mediated NF-kappaB activation, but severely impaired JNK activation (Lee et al., 1997). Fibroblasts from TRAF2 null mice show complete disruption of TNF-mediated JNK activation, but only quantitative abnormalities in TNF-induced NF-kappaB activation (Yeh et al., 1997). Thus, TRAF2 appears to be essential for JNK activation, but its role in NF-kappaB activation appears to be dispensable. RIP null mice have a more severe defect in TNF-mediated activation of NF-kappaB, and TRAF2 may act on the NF-kappaB pathway through its interactions with RIP.

TRAF2 null and TRAF2DN mice also provide evidence for a role of TRAF2 in apoptotic signaling pathways. Sensitivity to TNF induced cell death is increased in thymocytes and embryonic fibroblasts from TRAF2DN and TRAF2 null mice, suggesting that TRAF2 has an anti-apoptotic function distinct from that mediated by NF-kappaB. TRAF2 binds a number of proteins that inhibit apoptosis, including c-IAPs. c-IAP1 and c-IAP2 are mammalian proteins that are closely related to the inhibitor of apoptosis protein (IAP) family originally identified in baculoviruses. Both c-IAPs are recruited to TNFR2 through interaction with a TRAF1-TRAF2 heterocomplex (Rothe et al., 1995).

In addition to these functional studies using mutated TRAF2 proteins, nature has provided its own dominant negative TRAF2 protein in the form of TRAF2A, a splice variant of TRAF2. TRAF2A mRNA encodes an additional seven amino acid residues within the amino terminal RING finger domain of TRAF2 (Brink and Lodish, 1998). TRAF2A is unable to stimulate NF-kappaB activity when overexpressed in 293 cells and acts as a dominant inhibitor of TNFR2 mediated NF-kappaB activation. Furthermore TRAF2A has a short half life of approximately 100 min, but is stabilized by TRAF1 (and TRAF2), providing a further mechanism by which TRAF1 may act as a negative regulator of NF-kappaB activation.

TRAF3

TRAF3 was first described as a molecule that binds to the cytoplasmic tail of CD40. CD40 is expressed on many cell types, including B cells, dendritic cells, macrophages and monocytes, endothelial cells, smooth muscle cells and fibroblasts. CD40 is a receptor for CD40 ligand (CD 154), which is transiently expressed on activated CD4+ T cells. Signaling through CD40 in B cells induces rescue from apoptosis, proliferation, differentiation, Ig production, class switching and expression of co-stimulatory molecules. The interaction of TRAF3 with CD40 is ligand dependent (Kuhné et al., 1997), but binding of TRAF3 to CD40 in B cells is not necessary for the induction of antibody secretion (Hostager and Bishop, 1999). Rather, overexpression of TRAF3 inhibits CD40 mediated antibody secretion, and this effect was dependent on an intact TRAF binding site on CD40. A dominant negative N-terminal truncated TRAF3 is also inhibitory, suggesting that the physical association of TRAF3 with CD40 mediates its negative regulatory function. TRAF2 also binds to CD40 in a ligand dependent manner, but is not required for CD40 induction of antibody secretion. TRAF2 appears to play a positive role in B cell differentiation, but this activity is apparent even when its binding site on CD40 is disrupted.

Further evidence that TRAF3 is not required for CD40 signaling in B cells is provided by experiments using TRAF3 null mice. Mice deficient in TRAF3 are depleted in all lineages of peripheral leucocytes, and die shortly after birth (Xu et al., 1996). However, B cells from TRAF3-/- upregulate CD23 and proliferate normally in response to CD40 ligand stimulation, and fetal liver cells from TRAF3 deficient mice can reconstitute the immune system of irradiated wild type mice, although isotype switching in response to T-dependent antigens is defective. Thus TRAF3 is not required for CD40 signaling, but appears to be important in T cell-dependent immune responses.

These effects of TRAF3 may be mediated through other TNF receptor family members. TRAF3 was independently identified as a protein that interacts with the Epstein-Barr virus latent membrane protein, LMP1, and has since been shown to interact with several TNF receptor family members. Epstein-Barr virus causes proliferation of infected B lymphocytes through the expression of nuclear proteins and the integral membrane protein, LMP1, which is a constitutively active TNF receptor. The C-terminal cytoplasmic domain contains a site that binds TRAF3, and also TRAFs 1, 2 and 5, and mediates both EBV induced B cell proliferation and NF-kappaB activation (Izumi et al., 1999). TRAF3 is also recruited in a ligand dependent manner to the lymphotoxin-beta receptor (LTbetaR) and can have an inhibitory effect on NF-kappaB activation through LTbetaR. It is also involved in the induction of cell death by LT-beta (VanArsdale et al., 1997), and a dominant negative mutant of TRAF3 inhibits cell death signaling by lymphotoxin-beta, but not TNF (Force et al., 1997).

TRAF4

TRAF4 (originally designated CART1 because it contained a C-rich domain associated with RING and TRAF) was identified by differential screening of a cDNA library of breast cancer-derived metastatic lymph nodes (Régnier et al., 1995). TRAF4 localizes predominantly to the nucleus, and has not been shown to regulate signaling through cell surface receptors. In vitro binding assays have demonstrated that TRAF4 interacts weakly with LTbetaR, and weakly with the p75 nerve growth factor receptor, but not with TNFR1, TNFR2, Fas or CD40 (Krajewska et al., 1998). TRAF4 is highly expressed during embryogenesis in the mouse, most noticeably in the central and peripheral nervous system (Masson et al., 1998). In the adult mouse it is expressed in the hippocampus and olfactory bulb but not other normal tissues.

TRAF5

TRAF5 was identified as a protein that could interact with LTbetaR (Nakano et al., 1996) and CD40 (Ishida et al., 1996), and has subsequently been implicated in NF-kappaB activation by CD27 (Akiba et al., 1998) and CD30 (Aizawa et al., 1997). NF-kappaB is activated by overexpression of full-length TRAF5 but not a truncated form lacking the zinc binding region (Nakano et al., 1996). The same truncated TRAF5 mutant also partially inhibits NF-kappaB activation mediated by overexpression of LTbetaR, suggesting that TRAF5 is involved in LTbetaR signal transduction. Interaction of TRAF5 with CD40 is indirect, involving hetero-oligomerization with TRAF3 (Leo et al., 1999). An N-terminal deletion mutant of TRAF5 lacking the RING finger suppresses CD40 mediated CD23 expression (Ishida et al., 1996). Further evidence for a role of TRAF5 in CD40 signaling is provided by studies using cells from TRAF5 null mice. TRAF5 null mice are born healthy with no obvious defects (Nakano et al., 1999). Cells from these mutant mice display normal NFkappaB and JNK activation through CD27 or CD40, but CD27 or CD40 mediated lymphocyte activation was substantially impaired.

TRAF6

TRAF6 was initially identified as a signal transducer for IL-1 (Cao et al., 1996). Overexpression of TRAF6 activates NFkappaB, and a dominant negative mutant of TRAF6 inhibits NF-kappaB activation by IL-1 but not TNF. TRAF 6 also activates JNK and p38 when overexpressed (Song et al., 1997), and as with TRAF2 oligomerization of TRAF6 has been shown to be important for JNK activation (Baud et al., 1999). IL-1 induces recruitment of IRAK to activated receptors. IRAK becomes highly phosphorylated and then forms a complex with TRAF6 that is not associated with the receptor. After IL-1 stimulation TRAF6 can also exist in a separate complex with T6BP (TRAF6 binding protein). IRAK is not present in TRAF6-T6BP complexes, but is required for their formation (Ling and Goeddel, 2000). T6BP does not seem to play a direct role in NF-kappaB or JNK activation.

TRAF6 can activate IKK through interaction with a separate hetero-dimeric protein complex composed of the ubiquitin conjugating enzyme Ubc13 and the Ubc-like protein Uev1A. Ubiquitination of proteins involves an enzyme cascade composed of a ubiquitin activating enzyme, a ubiquitin conjugating enzyme, and a ubiquitin protein ligase. The RING finger domain of TRAF6 can function as a ubiquitin ligase, which, together with the Ubc13/Uev1A complex mediates polyubiquitination of an as yet unidentified protein that is involved in IKK activation (Deng et al., 2000).

TRAF6 also interacts with CD40, using a different site than TRAFs 1, 2 and 3. TRAF6 binds within the sequence 231QEPQEINF that has been mapped to a membrane proximal region (Pullen et al., 1998). Mutant CD40 molecules that eliminate interaction with TRAF 1, 2 and 3 or with TRAF6 have helped to define the role of TRAF6 in CD40 mediated signaling (Pullen et al., 1999). Mutations that eliminate TRAF6 binding but allow binding of TRAF1, 2 and 3 to CD40 diminish CD40 dependent NF-kappaB, JNK and p38 activation, whereas mutations that prevent binding of all TRAFs abolish JNK and p38 activation, but permit diminished NF-kappaB activation.

The abnormal phenotype of TRAF6 null mice relates predominantly to defective bone formation. Severe osteopetrosis with defects in bone remodeling and tooth eruption caused by impaired osteoclast formation are found in TRAF6 deficient mice which become runted, and die at an early age (Naito et al., 1999; Lomaga et al., 1999). Studies using cells derived from these mutant mice confirm the role of TRAF6 in IL-1 and CD40 mediated signaling. IL-1 induced activation of NF-kappaB and JNK in embryonic fibroblasts and IL-1 induced thymocyte proliferation are defective. In addition CD40 mediated NF-kappaB activation and proliferation in splenic B cells is significantly reduced.

Studies using embryonic fibroblasts from TRAF6 knockout mice have also defined a role for TRAF6 in IL17 signal transduction. IL17 fails to activate NF-kappaB and JNK in TRAF6 deficient cells, abolishing IL17 induced IL6 and intracellular adhesion molecule 1 expression (Schwandner et al., 2000). This defect can be overcome by restoration of TRAF6 to the cells by transient transfection.

Subcellular localization of TRAF proteins

TRAF proteins acts as intracellular adaptors that are recruited to different receptors, and the molecular basis for the functional interactions between different TRAFs and receptors have been characterized. The mechanism through which TRAF proteins move to different subcellular localizations is less clear, although there is evidence that TRAF proteins associate with different intracellular proteins that may facilitate their recruitment to cell surface receptor complexes. In addition, targeting of TRAF proteins to the nucleus may provide a mechanism for directly regulating transcriptional activity.

With the exception of TRAF4, TRAF proteins are cytosolic proteins, although overexpressed TRAF2, TRAF5 and TRAF6 predominantly localize to membrane containing cell fractions (Dadgostar and Cheng, 2000). TRAF4 predominantly localizes to the nucleus, but overexpressed TRAF4 can be found in the cytosol of transfected cells (Krajewska et al., 1998).

Endogenous TRAF2 is a cytosolic protein (Rothe et al., 1994), that is recruited to membrane associated receptors. TRAF2 interacts through its RING domain with the actin-binding protein filamin (Leonardi et al., 2000). Overexpression of filamin inhibits TRAF2-induced activation of NF-kappaB and JNK, and NF-kappaB activation induced by TNF, IL-1, Toll receptors and TRAF6, possibly by sequestering TRAF2 (and TRAF6) away from signaling complexes. In endothelial cells TRAF2 constitutively associates with the membrane organizing protein caveolin-1, and is recruited as part of a TRAF2-caveolin complex to TNF receptors (Feng et al., 2001). A fragment containing the RING and zinc fingers, can be targeted to the nucleus of endothelial cells, where it may directly regulate transcriptional regulatory activity (Min et al., 1998).

TRAF3 is linked to the microtubule network by MIP-T3 (Ling and Goeddel, 2000). MIP-T3 is a novel protein that binds to tubulin in vitro, and to Taxol-stabilized microtubules in cells. MIP-T3 recruits TRAF3 to microtubules when both proteins are overexpressed. CD40 ligand stimulation induces dissociation of TRAF3 from endogenous TRAF3-MIP-T3 complexes, and recruitment of TRAF3 to the CD40 receptor complex. Thus MIP-T3 may sequester TRAF3 to the cytoskeletal network, providing a mechanism through which it may be directed to different cellular compartments. Enforced membrane localization of TRAF3 through the addition of a myristolation signal is sufficient to convert it to a potent activator of JNK (Dadgostar and Cheng, 2000).

Tissue expression of TRAF proteins

Although considerable information has accumulated concerning the molecular structure and function of TRAF proteins, less is known about their expression and role in vivo. In mice TRAF1 is selectively expressed in spleen, lung and testis, whereas TRAF2, TRAF3, TRAF5 and TRAF6 are ubiquitously expressed (Rothe et al., 1995; Nakano et al., 1996; Ishida et al., 1996). The highest levels of TRAF2 are found in spleen. TRAF2A is ubiquitously expressed, but its expression relative to TRAF2 varies from very low in brain, lung and heart, to almost equivalent levels in spleen (Brink and Lodish, 1998). High levels of TRAF5 are observed in both spleen and lung. TRAF4 was identified through its selective expression in breast carcinoma, but can be detected in normal human adult thymic epithelial cells and lymph node dendritic cells, and the basal cell layer of most epithelia in the body (Krajewska et al., 1998).

The pattern of TRAF expression is altered in lymphoid malignancies, with certain cancer types displaying particular patterns of TRAF expression (Zapata et al., 2000). For example, upregulation of TRAF1 has consistently been reported in lymphoid malignancies (Zapata et al., 2000; Durkop et al., 1999; Izban et al., 2000), with increased expression of TRAF1 in Epstein-Barr virus-transformed lymphoid cells and Reed-Sternberg cells in Hodgkin's disease.

TRAF proteins thus physically and functionally connect cell surface receptors to signaling pathways involved in regulation of diverse cellular responses, which include activation, differentiation and survival. Considerable progress has been made towards understanding the molecular basis of their physical and functional interactions. The regulated expression of these proteins in normal and diseased tissues suggests that they play an important role in physiological and pathological processes.

Acknowledgements

JR Bradley is supported by the National Kidney Research Fund (UK).

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Tables

Table 1 TNF receptor family members

1 October 2001, Volume 20, Number 44, Pages 6482-6491
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