{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nToll-interacting protein (TOLLIP) is a multifunctional intracellular adaptor that plays a critical role in modulating innate immune receptor signaling. It directly associates with Toll-like receptors (TLR2 and TLR4) as well as the interleukin-1 receptor, where it interferes with downstream activation by potently inhibiting interleukin-1 receptor–associated kinase (IRAK) activity and NF-κB activation. Moreover, TOLLIP itself becomes phosphorylated upon receptor stimulation and interacts with additional signaling molecules (e.g., caveolin-1 and CD86), thereby fine-tuning the inflammatory output of immune cells."}, {"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": "\nIn addition to its signaling role, TOLLIP is integral to intracellular trafficking and protein homeostasis. It functions as an endosomal adaptor that binds ubiquitinated receptors—such as the interleukin-1 receptor and the transforming growth factor–β type I receptor—and directs them toward lysosomal degradation. Through its interaction with sorting factors like Tom1 and its affinity for phosphoinositides via its C2 domain, TOLLIP participates in cargo sorting. Furthermore, as the human homolog within a family of ubiquitin–Atg8 adaptors, it collaborates in selective autophagy to eliminate aggregation‐prone proteins and partners with the E3 ligase Parkin to regulate mitochondrial quality control."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic and functional studies have further revealed that TOLLIP influences disease susceptibility and progression across a spectrum of conditions. Variations in the TOLLIP gene associate with altered cytokine responses in infectious diseases such as tuberculosis and leprosy, and with aberrant inflammatory processes in pulmonary fibrosis, inflammatory bowel disease, and preeclampsia. Beyond infection and inflammation, TOLLIP has been implicated in cardiovascular remodeling, neuronal ischemic injury, and even in the regulation of canonical Wnt signaling. Collectively, these findings position TOLLIP as a multifaceted regulator that links receptor-mediated immune activation with endosomal sorting and autophagic clearance, offering novel therapeutic insights for infectious, inflammatory, neoplastic, and degenerative disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Y Bulut, E Faure, L Thomas, et al. 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