Recombinant Human TRAILR1/TNFRSF10A Fc Chimera Protein

Human TRAIL R1 (TNF-related apoptosis inducing ligand receptor 1), also called DR4 (death receptor 4), is a 50 ‑ 57 kDa, 468 amino acid (aa) type 1 transmembrane protein in the TNF R family, designated TNFRSF10A (1 ‑ 3). Of the five receptors for TRAIL (also called APO2 ligand) in humans, TRAIL R1/DR4 and TRAIL R2/DR5 are apoptosis-inducing and share 59% aa identity within the cytoplasmic death domain (aa 365 ‑ 448 of human TRAIL R1) (1 ‑ 3). Rodents do not express TRAIL R1/DR4. Human decoy receptors TRAIL R3 and TRAIL R4 have non-functional death domains but share ~60% aa identity with TRAIL R1 within extracellular TNFR domains (aa 107 ‑ 229), while the secreted TRAIL receptor osteoprotegerin shares only 18% aa identity with TRAIL R1. Trimeric TRAIL engagement of TRAIL R1 induces apoptosis by recruiting a cytosolic death-inducing signaling complex (DISC) that includes the adaptor FADD and caspases 8 and 10 (2 ‑ 6). TRAIL R1 translational modifications, such as O-glycosylation and palmitoylation, promote apoptosis by enhancing oligomerization and presence in lipid rafts, respectively (3 ‑ 6). Recombinant human TRAIL R1 neutralizes the ability of TRAIL to induce apoptosis (1). TRAIL R1 protein is expressed mainly in damaged, infected and malignant cells and can be repressed by hedgehog proteins in oncogenic cells (3, 7, 8). TRAIL R1 is also expressed on hemopoietic cells and influences activities such as monocyte migration (9). On senescent neutrophils, CXCL12/SDF-1 engagement of CXCR4 induces expression of all TRAIL R (7). TRAIL functions in immune surveillance, inducing apoptosis in cancer cells but not normal cells (3, 10, 11). TRAIL R1 surface expression correlates more closely than that of TRAIL R2 with TRAIL induction of apoptosis on tumor cells such as melanoma and chronic lymphocytic and acute myeloid leukemias (6, 12, 13).