{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFRSF10B, more commonly known as death receptor 5 (DR5), is a key transmembrane receptor that, upon engagement by its ligand TRAIL (TNF‐related apoptosis‐inducing ligand), triggers apoptosis via the extrinsic pathway. DR5 signaling is initiated by the recruitment of adaptor molecules such as FADD and subsequent activation of caspase‑8, which orchestrates a caspase cascade leading to cell death. Moreover, DR5 can be upregulated and activated independently of extracellular ligand binding during persistent endoplasmic reticulum stress – a process regulated by stress inducible transcription factors (e.g. CHOP) – and even directly by interactions with misfolded proteins. This intrinsic “inner‐cell” activation integrates stress signals with the apoptotic machinery and sensitizes cells to death signals in various contexts, including those induced by interferon‐α and bile acids."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural studies of DR5 have demonstrated that the receptor assembles as a trimer upon ligand binding, a configuration that is essential for the formation of the death‐inducing signaling complex (DISC). Detailed crystallographic and biophysical analyses have elucidated not only the extracellular binding interfaces by which TRAIL and agonistic ligands interact with DR5 but also revealed that the transmembrane helix itself can mediate higher‐order receptor clustering. This clustering, which is further modulated by specific interactions with adaptor molecules such as FADD, is critical for efficient caspase activation and subsequent induction of apoptosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer cells, numerous therapeutic agents and strategies have been shown to modulate DR5 expression and activity. A variety of small molecules, natural products (such as resveratrol, luteolin, and quercetin), proteasome inhibitors, as well as engineered TRAIL or receptor‐selective variants and agonistic antibodies (for example, Apomab) have been reported to enhance DR5 expression and redistribute the receptor into lipid raft microdomains, thereby sensitizing resistant tumors to apoptosis. In addition, studies have uncovered that the antiapoptotic milieu—mediated by proteins like survivin or c‐FLIP—and specific microRNAs (for instance, miR‑1246) can suppress DR5 levels, thereby contributing to tumor cell survival. Thus, overcoming such regulatory blocks on DR5 function is emerging as a promising strategy to boost therapeutic efficacy against neoplastic cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in apoptosis induction and cancer therapeutics, DR5 is also implicated in various pathological and immunological contexts. Aberrant DR5 expression has been observed in settings such as chronic viral infections, autoimmune diseases, and inflammatory conditions, where it contributes to the regulation of immune cell homeostasis and the elimination of infected or aberrantly activated cells. For instance, enhanced DR5 on hepatocytes or synovial fibroblasts can predispose these cells to TRAIL‐mediated apoptosis—a mechanism that may underlie T cell tolerance in the liver during hepatitis, immune regulation in HIV infection, or joint destruction in rheumatoid arthritis. Moreover, defective DR5 signaling due to overexpression of inhibitory proteins like c‐FLIP has been linked to resistance in certain malignancies, underscoring its tumor‐suppressor functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Masaya Shigeno, Kazuhiko Nakao, Tatsuki Ichikawa, et al. 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