{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTBK1 is a central, non‐canonical kinase that orchestrates innate immune signaling. It mediates the phosphorylation and activation of key transcription factors—including IRF3 and NF‑κB—downstream of cytosolic nucleic acid sensors such as cGAS–STING and Toll‑like receptors, thereby driving type I interferon and proinflammatory cytokine production. TBK1 function is regulated via its dynamic interactions with adaptor proteins (for example, TANK, NAP1, Sintbad) and is subject to modulation by both auto‐phosphorylation and ubiquitin‐editing events. In addition, several viral proteins (e.g. Ebola VP35, hepatitis C virus NS3, hantavirus factors, and PEDV nucleocapsid) have evolved to interact with or sequester TBK1 to inhibit these innate immune responses, underscoring its critical antiviral role."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in antiviral cytokine induction, TBK1 is a pivotal regulator of selective autophagy. By phosphorylating autophagy receptors such as optineurin (OPTN), p62, NDP52, and TAX1BP1, TBK1 enhances the targeting and engulfment of ubiquitinated cargo, including damaged mitochondria and intracellular pathogens. This process facilitates mitophagy and other forms of cargo-specific autophagy, integrating cellular stress responses with immune defense and linking TBK1 activity to the regulation of cellular homeostasis. Moreover, cellular pathways that sense mechanical or nutritional status (for example, via YAP/TAZ in the Hippo pathway) further modulate TBK1’s autophagic and signaling outputs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its immunomodulatory and autophagic functions, TBK1 plays key roles in cell survival, cancer progression, and neurodegeneration. TBK1 supports the viability of KRAS‐mutant cancer cells through activation of NF‑κB and, by engaging pathways such as AKT signaling, contributes to oncogenic transformation. Conversely, loss‐of‐function mutations or altered gene dosage of TBK1 are strongly implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and normal tension glaucoma. These findings underscore the delicate balance maintained by TBK1 activity, as both its hyperactivation and insufficiency can have profound physiological consequences."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Katherine A Fitzgerald, Sarah M McWhirter, Kerrie L Faia, et al. 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