Identification of tumour necrosis factor apoptosis inducing ligand (TRAIL), a TNF family ligand, sparked a torrent of research, following an initial observation that it could kill tumour cells, but spare normal cells. Almost a decade after its discovery, and with five known receptors, the true physiological role of TRAIL is still debated and its anti-tumorigenic properties limited by potential toxicity. This review takes a comprehensive look at the story of this enigmatic ligand, addressing its remaining potential as a therapeutic and providing an overview of the TRAIL receptors themselves.

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant systemic autoinflammatory disease associated with heterozygous mutations in TNF receptor 1 (TNFR1). Here we examined the structural and functional alterations caused by 9 distinct TRAPS-associated TNFR1 mutations in transfected cells and a mouse "knock-in" model of TRAPS. We found that these TNFR1 mutants did not generate soluble versions of the receptor, either through membrane cleavage or in exosomes. Mutant receptors did not bind TNF and failed to function as dominant-negative inhibitors of TNFR1-induced apoptosis. Instead, TRAPS mutant TNFR1 formed abnormal disulfide-linked oligomers that failed to interact with wild-type TNFR1 molecules through the preligand assembly domain (PLAD) that normally governs receptor self-association. TRAPS mutant TNFR1 molecules were retained intracellularly and colocalized with endoplasmic reticulum (ER) markers. The capacity of mutant receptors to spontaneously induce both apoptosis and nuclear factor kappaB (NF-kappaB) activity was reduced. In contrast, the R92Q variant of TNFR1 behaved like the wild-type receptor in all of these assays. The inflammatory phenotype of TRAPS may be due to consequences of mutant TNFR1 protein misfolding and ER retention.

TRAIL, tumor necrosis factor-related apoptosis-inducing ligand, is a member of the TNF family of proteins. Tumour cells were initially found to have increased sensitivity to TRAIL compared with normal cells, raising hopes that TRAIL would prove useful as an anti-tumor agent. The production of reliable monoclonal antibodies against TRAIL and its receptors that can stain fixed specimens will allow a thorough analysis of their expression on normal and malignant tissues. Here we report the generation of monoclonal antibodies against TRAIL and its four membrane-bound receptors (TR1-4), which have been used to stain a range of normal and malignant cells, as routinely fixed specimens. Low levels of TRAIL expression were found to be limited mostly to smooth muscle in lung and spleen as well as glial cells in the cerebellum and follicular cells in the thyroid. Expression of the TRAIL decoy receptors (TR3 and 4) was not as widespread as indicated by Northern blotting, suggesting that they may be less important for the control of TRAIL cytotoxicity than previously thought. TR1 and TR2 expression increases significantly in a number of malignant tissues, but in some common malignancies their expression was low, or patchy, which may limit the therapeutic role of TRAIL. Taken together, we have a panel of monoclonal antibodies that will allow a better assessment of the normal role of TRAIL and allow assessment of biopsy material, possibly allowing the identification of tumors that may be amenable to TRAIL therapy.

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A proliferation-inducing ligand (APRIL) (also known as TALL-2 and TRDL-1) is a member of the tumor necrosis factor (TNF) superfamily that has tumorigenic properties but is also important for the induction of humoral immune responses. APRIL binds two TNF receptors: transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA) as well as heparan sulfate proteoglycans (HSPGs). The aim of this study was to clarify the role of the HSPG interaction in canonical APRIL signaling, because it has been proposed to act as a docking site and also to play a role in direct signaling. In this study, we generated point mutants of soluble APRIL that lack either the capacity to bind HSPGs or TACI and BCMA and then tested the function of these mutants in mouse B-cell assays. In contrast to previous reports, we found that APRIL alone is sufficient to costimulate B-cell proliferation and drive IgA production and does not require artificial antibody cross-linking. We found no evidence that APRIL requires signaling through HSPGs but, notably, were able to show that binding of APRIL to HSPGs is crucial for mediating natural APRIL cross-linking to allow for optimal activation of murine B cells.

APRIL (A proliferation-inducing ligand) is a TNF family member that binds two TNF receptor family members, TACI and BCMA. It shares these receptors with the closely related TNF family member, B-cell activating factor (BAFF). Contrary to BAFF, APRIL binds heparan sulfate proteoglycans (HSPGs), which regulates cross-linking of APRIL and efficient signaling. APRIL was originally identified as a growth promoter of solid tumors, and more recent evidence defines APRIL also as an important survival factor in several human B-cell malignancies, such as chronic lymphocytic leukemia (CLL). To target APRIL therapeutically, we developed two anti–human APRIL antibodies (hAPRIL.01A and hAPRIL.03A) that block APRIL binding to BCMA and TACI. Their antagonistic properties are unique when compared with a series of commercially available monoclonal anti–human APRIL antibodies as they prevent in vitro proliferation and IgA production of APRIL-reactive B cells. In addition, they effectively impair the CLL-like phenotype of aging APRIL transgenic mice and, more importantly, block APRIL binding to human B-cell lymphomas and prevent the survival effect induced by APRIL. We therefore conclude that these antibodies have potential for further development as therapeutics to target APRIL-dependent survival in B-cell malignancies.

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TNF receptor-associated periodic syndrome (TRAPS) is a dominantly inherited disease caused by missense mutations in the TNF receptor 1 (TNFR1) gene. Patients suffer from periodic bouts of severe abdominal pain, localised inflammation, migratory rashes, and fever. More than 40 individual mutations have been identified, all of which occur in the extracellular domain of TNFR1. In the present review we discuss new findings describing aberrant trafficking and function of TNFR1 harbouring TRAPS mutations, challenging the hypothesis that TRAPS pathology is driven by defective receptor shedding, and we suggest that TNFR1 might acquire novel functions in the endoplasmic reticulum, distinct from its role as a cell surface receptor. We also describe the clinical manifestations of TRAPS, current treatment regimens, and the widening array of patient mutations. IntroductionThe TNF-receptor associated periodic syndrome (TRAPS) is a dominantly inherited periodic fever syndrome characterised by prolonged episodic fevers, multiorgan involvement, and resistance to colchicine. Over 40 missense mutations in TNF receptor 1 (TNFR1), the prototypical proinflammatory receptor, have been associated with TRAPS. In the present review we discuss recent evidence that the unifying molecular defect in TRAPS-associated mutant TNFR1 is receptor misfolding and retention in the endoplasmic reticulum (ER). This finding constitutes a novel mechanism of receptor misbehaviour in genetic disease and suggests hitherto unexpected functions for intracellularly retained receptors in promoting inflammation. Periodic fevers and TRAPSThe periodic fevers are a group of disorders characterised by unprovoked attacks of fever and localised inflammation that can affect multiple organ systems [1]. There are several periodic fever syndromes that are inherited in a recessive manner, such as familial Mediterranean fever (FMF) caused by mutations in the gene encoding the neutrophil-specific protein Pyrin [2]. Most evidence currently suggests that pyrin negatively regulates the production of IL-1β -a major proinflammatory cytokine of the innate immune response [3]. IL-1β is generated from its proform via cleavage by caspase-1, which occurs in a specialised IL-1 activating protein complex termed the inflammasome [4][5][6]. FMF-associated mutations in pyrin are thought to exert less inhibition of IL-1β processing [7]. Another such recessive disease is hyperimmunoglobulinemia-D with periodic fever syndrome, which arises due to mutations in mevalonate kinase -a key enzyme in cholesterol biosynthesis and the synthesis of nonsterol isoprenoid molecules [8,9]. The exact molecular basis for the disease resulting from these mutations, however, remains unclear.The molecular basis of two groups of dominant periodic fever syndrome has been identified. Dominant mutations in the CIAS1 gene are associated with a heterogeneous group of inflammatory conditions encompassing Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and the neonatal onset multisystem inflamma...