Identification of a New Murine Tumor Necrosis Factor Receptor Locus That Contains Two Novel Murine Receptors for Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)

Abstract

Tumor necrosis factor (TNF) ligand and receptor superfamily members play critical roles in diverse developmental and pathological settings. In search for novel TNF superfamily members, we identified a murine chromosomal locus that contains three new TNF receptorrelated genes. Sequence alignments suggest that the ligand binding regions of these murine TNF receptor homologues, mTNFRH1, -2 and -3, are most homologous to those of the tumor necrosis factor-related apoptosisinducing ligand (TRAIL) receptors. By using a number of in vitro ligand-receptor binding assays, we demonstrate that mTNFRH1 and -2, but not mTNFRH3, bind murine TRAIL, suggesting that they are indeed TRAIL receptors. This notion is further supported by our demonstration that both mTNFRH1:Fc and mTNFRH2:Fc fusion proteins inhibited mTRAIL-induced apoptosis of Jurkat cells. Unlike the only other known murine TRAIL receptor mTRAILR2, however, neither mTNFRH2 nor mTNFRH3 has a cytoplasmic region containing the well characterized death domain motif. Coupled with our observation that overexpression of mTNFRH1 and -2 in 293T cells neither induces apoptosis nor triggers NF B activation, we propose that the mTnfrh1 and mTnfrh2 genes encode the first described murine decoy receptors for TRAIL, and we renamed them mDcTrailr1 and -r2, respectively. Interestingly, the overall sequence structures of mDcTRAILR1 and -R2 are quite distinct from those of the known human decoy TRAIL receptors, suggesting that the presence of TRAIL decoy receptors represents a more recent evolutionary event.In many biological systems, cellular outcomes are often determined by environmental cues delivered through ligand and receptor interactions on the cell surface. One group of ligand/ receptor pairings critical to this decision-making process is the tumor necrosis factor (TNF) 1 ligand and receptor superfamily (1). Upon ligand engagement, TNF receptors trigger intracellular signaling pathways that lead to cell proliferation, differentiation, or apoptosis. The pivotal roles of these TNF ligands and receptors across diverse biological areas are perhaps best illustrated by gene knockout studies demonstrating the essential involvement of the lymphotoxin pathway in lymphoorganogenesis (2, 3), the BAFF pathway in B-cell development (4), the RANKL pathway in osteoclastogenesis (5), and the EDA pathway in hair-follicle formation (6). The ability of many members of this family to regulate both innate and adaptive immunity also makes them attractive targets for therapeutic intervention of various immune disorders, as exemplified by the success of anti-TNF therapy in treating rheumatoid arthritis and Crohn's disease (7).TNF receptor family members are characterized by the presence of cysteine-rich repeats (CRDs) in their extracellular domains (8, 9). A CRD typically contains two structural motifs, called modules, that are stabilized by disulfide bridges formed between the cysteine residues. The linear arrangement of modules creates a scaffold that supports the unusual elongated structures seen...

Enforced covalent trimerization increases the activity of the TNF ligand family members TRAIL and CD95L

“…5,13,14 Thus, in KB cells that express TRAILR1 and TRAILR2, non-crosslinked TRAIL trimers already significantly induce cell death via the TRAILR1, whereas TRAILR1-mediated cell death is not relevant in the murine L929 cell line, because in mice only a homolog of human TRAILR2 exists. 15,16 In fact, in human Jurkat cells, which express only TRAILR2, noncrosslinked Flag-hTRAIL(95-291) is also practically inactive (Figure 2c). …”

Regulatory functions of TRAIL in hematopoietic progenitors: human umbilical cord blood and murine bone marrow transplantation

“…Following these observations, we monitored the dynamics of murine TRAIL receptor-2 after transplantation, this being the only known murine receptor for TRAIL that corresponds to human DR5. 20,21 We found that signaling by the murine receptor is trophic in nature.…”

“…[17][18][19] Among the known five TRAIL receptors, DR4 (TRAIL-R1) and DR5 (TRAIL-R2) are associated with transduction of apoptotic signals in humans, 16 whereas mice express only TRAIL-R2. 20,21 Although mRNA encoding TRAIL receptors DR4 and DR5 is frequently detected in CD34 þ progenitors, these cells were insensitive to apoptosis 22,23 even in the presence of low doses of doxorubicin. 24 Consistently, infusion of soluble TRAIL into rodents was not associated with gross abnormalities in hematopoiesis, 25,26 and TRAIL neither induced nor impaired the clonogenic activity of human hematopoietic progenitors in vitro.…”

FLICE-Like Inhibitory Protein Blocks Transforming Growth Factor β1–Induced Caspase Activation and Apoptosis in Prostate Epithelial Cells

“…Specifically, because TRAIL kills neoplastic and normal human prostate epithelial cells (18) via activation of the apical caspases (43), we examined its role in TGFh1-mediated apoptosis. Human TRAIL can bind two death-inducing receptors, DR4 and DR5, as well as three decoy receptors and OPG (44), but the DR4 receptor does not exist in rodents (45). Fc fusions of the extracellular domains of these receptors block TRAIL-induced cell death (18).…”