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(Chest. 1999;116:69S-73S.)
© 1999 American College of Chest Physicians

Signal Transduction by Tumor Necrosis Factor*

The Parker B. Francis Lectureship

David V. Goeddel, PhD

* From Tularik Inc, South San Francisco, CA 94080.

Correspondence to: David V. Goeddel, PhD, Tularik Inc, Two Corporate Dr, South San Francisco, CA 94080; e-mail: goeddel{at}tularik.com


   Introduction
TOP
 Introduction
Two TNF Receptors
 TNF Receptor 2 Signaling...
 TNF Receptor 1 Signaling...
 Conclusions
 References
 
Tumor necrosis factor (TNF) is the name of an activity produced by activated macrophages that induced hemorrhagic necrosis of transplanted tumors in mice and killed transformed cell lines in culture.1 These and other early studies showing anticancer potential led several laboratories to begin efforts to molecularly characterize TNF. Human TNF was purified and its complementary DNA cloned in 1984.2 TNF is initially synthesized as a preprotein of 233 amino acids, from which the N-terminal 76 amino acids are later removed. The 157 amino acid mature form of TNF exists as a 52-kd trimer of identical subunits.3 4

The availability of pure recombinant TNF permitted many studies of its biological properties in the late 1980s. TNF is now known to be a pleiotropic cytokine with many beneficial and harmful actions. In addition to its activities described above, it is a major mediator of immune regulation and inflammatory responses. It has antiviral, mitogenic, and numerous other activities.5 6 TNF entered clinical trials in the late 1980s as an anticancer agent, but its systemic toxicity has limited its anticancer efficacy to date. Recently, efforts have been directed at blocking the actions of TNF since inappropriate production of TNF is clearly associated with a number of disease states.6 7


   Two TNF Receptors
TOP
 Introduction
 Two TNF Receptors
TNF Receptor 2 Signaling...
 TNF Receptor 1 Signaling...
 Conclusions
 References
 
The activities of TNF are signaled by two distinct cell surface receptors.8 9 10 11 TNF receptor 1 (TNF-R1) and TNF receptor 2 (TNF-R2) share 28% identity in their extracellular ligand-binding domains. TNF binding induces receptor trimerization,12 which initiates the signal transduction process.13 14 TNF-R1 and TNF-R2 belong to the large TNF receptor superfamily that is defined by the cysteine-rich architecture of the ligand-binding region.15

TNF-R1 and TNF-R2 are coexpressed on most cell types. Transfection experiments, receptor-specific antibodies, and experiments with gene knock-out mice have shown that TNF-R1 is the dominant signaling receptor.13 14 TNF-R1 can signal apoptosis and activate the transcription factor nuclear factor-kappa B (NF-{kappa}B). TNF-R2 can directly signal certain activities in lymphocytes such as NF-{kappa}B activation, and also plays an auxiliary role by helping deliver TNF to TNF-R1.16

The intracellular domains (ICDs) of the TNF receptor family do not specify enzymatic activity and are largely unrelated to each other, with the primary amino acid sequences of the ICDs of the two TNF receptors being completely unrelated. However, the identification of several TNF-receptor-associated proteins and studies of their assembly into signaling complexes have advanced our knowledge in this area. Common themes for signaling by the entire superfamily have emerged from studies of the two distinct TNF receptor complexes.


   TNF Receptor 2 Signaling Complex
TOP
 Introduction
 Two TNF Receptors
 TNF Receptor 2 Signaling...
TNF Receptor 1 Signaling...
 Conclusions
 References
 
The mouse cytotoxic T-cell line contains TNF-R2, but not TNF-R1. Murine TNF triggers proliferation and NF-{kappa}B activation in these cells. These same activities are seen in response to human TNF in stably transfected CT6 cells that express human TNF-R2. The study of deletion mutants of TNF-R2 in CT6 cells resulted in the identification of a 78 amino acid region in the ICD that was required for signaling.17 Proteins of 45, 56, 66, and 68 kd were found to bind to this region of TNF-R2 and were purified by affinity chromatography.17 18

The 45- and 56-kd proteins were called TRAF1 and TRAF2, respectively.17 Protein sequencing and complementary DNA cloning experiments revealed that TRAF1 and TRAF2 were novel proteins that contained a conserved C-terminal "TRAF" domain of about 230 amino acids. The TRAF domain can be further divided into two subdomains, TRAF-N and TRAF-C, which share approximately 33% and 63% sequence identity, respectively. TRAF1 and TRAF2 can form both homodimers and heterodimers through their TRAF domains, but only TRAF2 interacts directly with TNF-R2.17 This interaction occurs via the TRAF-C subdomain.19 20 Thus, our initial purification of TRAF1 was a consequence of the TRAF2-TRAF1 heterodimer associating with TNF-R2. Northern blots demonstrate that TRAF2 expression is ubiquitous, whereas TRAF1 is expressed in a tissue-specific fashion. Therefore, depending on cell type, either a TRAF2-TRAF2 or a TRAF1-TRAF2 complex can be found in association with TNF-R2.

The 68- and 66-kd proteins that were affinity purified were given the names cellular inhibitor of apoptosis protein 1 and 2, or c-IAP1 and c-IAP2, respectively.18 These proteins are structurally similar to baculoviral inhibitors of apoptosis proteins (IAPs), which are only about 30 kd in size, but like the mammalian c-IAPs, contain a C-terminal RING finger and an N-terminal baculovirus IAP repeat (BIR) motif. Since baculovirus IAPs prevent apoptosis of virally infected insect cells,21 it is likely that the mammalian c-IAPs are also involved in providing protection against cell death. c-IAP1 messenger RNA is expressed in all tissues examined, whereas the expression of c-IAP2 is expressed preferentially in cells of the immune system.18 Neither c-IAP1 nor c-IAP2 interacts with TNF-R2 directly. The BIR motifs of the cIAPs interact with the TRAF-N domains of both TRAF1 and TRAF2. The TRAF1-TRAF2 heterodimer recruits both c-IAP1 and c-IAP2 to the TNF-R2 complex.18

TNF-R2 is capable of signaling NF-{kappa}B activation in some cell types. Therefore, we overexpressed the four individual proteins in human 293 cells in an attempt to mimic TNF-induced receptor aggregation. Only TRAF2 was found to activate NF-{kappa}B when overexpressed. A TRAF2 mutant lacking its N-terminal RING finger behaved as a dominant negative mutant and acted as an inhibitor of TNF-R2 mediated NF-{kappa}B activation.19 TRAF2 can also activate the signaling pathway leading to activation of the Jun N-terminal kinase (JNK).22

TNF-R2, TRAF1, TRAF2, and the c-IAPs form a TNF-R2 complex when overexpressed in a process that is TNF independent.18 To determine whether the TRAFs and c-IAPs are associated with TNF-R2 under physiologic conditions, endogenous TNF-R2 was examined by immunoprecipitation in nontransfected CT6 cells before and after TNF treatment. The TNF-R2 immunocomplex contained TRAF2 only after TNF treatment (unpublished results). Since TRAF2 is required for other components of the TNF-R2 complex to interact with the receptor, the entire signaling complex (Fig 1) must be assembled in a ligand-dependent process.



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  		Figure 1. TNF-R2 signaling complex. See text for details.

 

   TNF Receptor 1 Signaling Complex
TOP
 Introduction
 Two TNF Receptors
 TNF Receptor 2 Signaling...
 TNF Receptor 1 Signaling...
Conclusions
 References
 
TNF-R1 contains a death domain of approximately 80 amino acids in its ICD that signals two important activities: apoptosis and NF-{kappa}B activation.23 24 A search for proteins that interact with the ICD of TNF-R1 resulted in the identification of TNF receptor-associated death domain (TRADD), a 34-kd cytoplasmic protein that contains a C-terminal death domain with 30% sequence identity to the death domain of TNF-R1.24 TNF-R1 and TRADD interact via their respective death domains, which are also capable of self-association. Overexpression of TRADD induces apoptosis and activates NF-{kappa}B. TRADD and TNF-R1 are not preassociated, but interact following TNF-mediated receptor aggregation.25

Additional components of the TNF-R1 apoptosis and NF-{kappa}B activation pathways were identified by two-hybrid screens utilizing TRADD as "bait." The proteins TRAF2, Fas-associated death domain (FADD), and receptor interacting protein (RIP) were obtained. Each of these proteins appears to play a role in TNF-R1 signaling.25 26 In addition, c-IAP1 is also a component of the TNF-R1 complex as it is present in immunoprecipitates of TNF-R1.27 A proposed role for each of these proteins in TNF-R1 signaling is discussed below.

TRAF2
The N-terminal domain of TRADD interacts with the TRAF-C domain of TRAF2, and the death domain of TRADD interacts with the death domain of TNF-R1.25 These results suggested that TRADD might function as an adapter protein that could simultaneously bind TRAF2 and TNF-R1. This prediction has been confirmed in both overexpression25 and endogenous systems.27 The presence of TRAF2 in the TNF-R1 complex suggested that it may play a similar role in TNF-R1 and TNF-R2 signaling. Overexpression of an N-terminal deletion mutant of TRAF2 inhibited NF-{kappa}B activation by TNF-R1, but had no effect on apoptosis.25 These results suggested that TRAF2 plays a role in NF-{kappa}B activation by both TNF receptors, but it is probably not involved in the signaling of apoptosis.

Gene targeting was performed to generate mice lacking TRAF2.28 These mice appeared normal at birth, but became runted and died prematurely. Thymocytes and fetal liver hematopoietic progenitors were sensitive to TNF-induced cell death. TRAF2-deficient embryonic fibroblasts had defective JNK activation, but near normal NF-{kappa}B activation in response to TNF treatment. These results demonstrated that a TRAF2-independent pathway exists for TNF-induced NF-{kappa}B activation.

FADD
FADD is a cytoplasmic death domain-containing protein that interacts with the death domain of Fas, a member of the TNF receptor superfamily.29 30 FADD also has an N-terminal death effector domain. The death effector domain of FADD recruits the cysteine protease caspase-8 to the Fas signaling complex where caspase-8 is activated and initiates Fas-mediated apoptosis.31 32 33

The death domains of TRADD and FADD interact efficiently. FADD does not interact directly with TNF-R1, but is recruited by TRADD to the TNF-R1 complex when all three proteins are overexpressed.25 This suggests that death domains can form complexes larger than dimers, and that FADD may be involved in TNF-R1 mediated signaling. A deletion mutant of FADD lacking its N-terminal 79 amino acids is a potent inhibitor of TNF-R1-mediated cell death, but has no effect on TNF-R1-mediated NF-{kappa}B activation, indicating that FADD is not a part of the latter pathway.25 Despite considerable effort, we were unable to demonstrate that FADD is a part of the TNF-R1 complex in nontransfected cells (unpublished results). To address this question, we generated FADD-deficient mice. These mice died before 11.5 days of gestation.34 However, FADD null mutant embryonic fibroblasts were examined. TNF-R1 activation did not induce apoptosis in these cells, demonstrating that FADD is required for TNF-mediated apoptosis.

RIP
RIP is a cytoplasmic serine/threonine protein kinase that contains a C-terminal death domain. It was originally described as a Fas-interacting protein.35 Our characterization of RIP suggests that it does not interact with Fas in mammalian cells.26 Rather, TRADD interacts strongly with RIP and recruits RIP to the TNF-R1 complex. Following TNF treatment, RIP is recruited to the TNF-R1 complex in nontransfected cells.26

RIP activates NF-{kappa}B26 and JNK22 when overexpressed. Both activities seem to reside in the kinase and intermediate domains.22 26 The C-terminal death domain of RIP is a very effective dominant negative inhibitor of TNF-induced NF-{kappa}B and JNK activation. These data suggested a model in which RIP is required for TNF-mediated activation of NF-{kappa}B and JNK. However, gene targeting experiments demonstrated that RIP deficiency results in defective TNF-induced NF-{kappa}B activation but does not affect TNF-induced JNK activation.36

c-IAP1
Following TNF treatment, the endogenous TNF-R1 complex from HeLa and U937 cells contains c-IAP1.27 Prior to TNF-treatment, c-IAP1 is found complexed with TRAF2, suggesting that TRAF2 recruits c-IAP1 to TNF-R1. Reconstitution experiments confirm that c-IAP1 recruitment to TNF-R1 requires both TRADD and TRAF2.27 The role of c-IAP1 in TNF-R1 signaling remains uncertain at this time. However, overexpression of c-IAP1 and c-IAP2 together blocks TRADD-mediated apoptosis (unpublished results).

SODD
Since the death domain of TNF-R1 can self-associate, a mechanism must exist that prevents unregulated receptor aggregation and signaling. Yeast two-hybrid interaction cloning experiments identified silencer of death domains (SODD) as a 60-kd protein that performs this function.37 SODD directly interacts with the death domain of TNF-R1 under normal physiologic conditions. When TNF-R1 is bound to SODD, it cannot simultaneously interact with TRADD. A direct signaling role of SODD has not yet been demonstrated.

Assembly of the TNF-R1 Signaling Complex
In our model for the TNF-R1 signaling complex, TNF-R1 is associated with SODD prior to its interaction with TNF. Following TNF treatment, TNF-R1 trimerizes and SODD is released from the receptor.37 The death domains of TNF-R1 then associate and stabilize the aggregated receptor. TRADD, which normally exists as either a monomer or dimer, is thus able to associate with the death domain of TNF-R1. This interaction allows TRADD to become an adapter protein that binds and recruits other signaling proteins. The N-terminus of TRADD recruits TRAF2 and the death domain of TRADD recruits RIP and FADD to the TNF-R1 complex. Each of these three recruited proteins activates a distinct signaling pathway. A model of the assembly process for the TNF-R1 complex is shown in Figure 2 .



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  		Figure 2. Sequential assembly of TNF-R1 signaling complex. See text for details.

 

   Conclusions
TOP
 Introduction
 Two TNF Receptors
 TNF Receptor 2 Signaling...
 TNF Receptor 1 Signaling...
 Conclusions
References
 
The mechanisms by which TNF signals so many diverse responses have begun to be elucidated through studies of the two TNF receptors and their associated signaling proteins. Various combinations of three distinct classes of signaling proteins, the TRAFs, c-IAPs, and death domain-containing proteins are recruited to the receptors in TNF-dependent processes. The composition of a signaling complex in a given cell type is dependent on many factors and is likely to influence important cellular decisions, such as whether the cell will undergo apoptosis or activate genes involved in the inflammatory response. Finally, lessons learned from study of the TNF receptor complexes provide a paradigm for signaling mechanisms utilized by other members of the TNF receptor superfamily.


   References
TOP
 Introduction
 Two TNF Receptors
 TNF Receptor 2 Signaling...
 TNF Receptor 1 Signaling...
 Conclusions
 References
 

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