| Functional area | Key concepts/definition | Core molecular mechanism | Key substrates/partners | Subcellular localization | Representative 2023-2024 sources (with DOI URLs) |
|---|---|---|---|---|---|
| Innate immune signaling (STING/MAVS→TBK1→IRF3/7) | TBK1 is a human serine/threonine kinase and central effector of nucleic-acid sensing that couples STING or MAVS signalosomes to type I interferon output; activation requires dimerization/oligomerization and Ser172 trans-autophosphorylation (pqac-00000004, pqac-00000006, pqac-00000007) | STING oligomerization on post-Golgi membranes recruits TBK1 dimers, enabling trans-autophosphorylation at S172 and phosphorylation of IRF3/IRF7; MAVS/TLR pathways likewise recruit TBK1 through adaptors such as TANK, NAP1/AZI2, and SINTBAD/TBKBP1 to drive IFN and some NF-κB responses (pqac-00000004, pqac-00000006, pqac-00000007, pqac-00000008) | STING, MAVS, TANK, NAP1/AZI2, SINTBAD/TBKBP1, IRF3, IRF7; K63-linked ubiquitination at Lys30/Lys401 contributes to activation (pqac-00000004, pqac-00000007) | Cytosol; ER-to-post-Golgi STING signalosomes; pathogen-sensing complexes (pqac-00000004, pqac-00000006) | Miranda et al., 2024, Trends Cancer, https://doi.org/10.1016/j.trecan.2024.02.007; Lin et al., 2023, Nat Commun, https://doi.org/10.1038/s41467-023-43419-4; Wegner et al., 2023, Front Immunol, https://doi.org/10.3389/fimmu.2023.1073608 (pqac-00000004, pqac-00000010) |
| Autophagy/mitophagy | TBK1 is a selective-autophagy/mitophagy kinase that amplifies ubiquitin-driven recruitment of cargo receptors and early autophagosome machinery; OPTN can act as a platform for TBK1 activation at mitophagy contact sites (pqac-00000002, pqac-00000006, pqac-00000008) | Upon mitochondrial damage or ubiquitinated cargo accumulation, TBK1 is recruited by OPTN/NDP52/TAX1BP1-containing assemblies; TBK1 autophosphorylation activates phosphorylation of mitophagy receptors, increasing their binding to ubiquitin, ATG8 proteins, and FIP200, thereby promoting phagophore assembly and cargo clearance (pqac-00000001, pqac-00000002, pqac-00000006, pqac-00000008) | OPTN, NDP52/CALCOCO2, TAX1BP1, FIP200, LC3/ATG8 family, ATG9A, RAB7A; OPTN sites include S177 and S473 in the LIR/UBAN region (pqac-00000002, pqac-00000006, pqac-00000008) | Damaged mitochondria; mitochondria–autophagosome formation contact sites; ubiquitin-coated bacteria/cargo; lysosome-associated autophagy initiation complexes (pqac-00000002, pqac-00000006, pqac-00000008) | Yamano et al., 2024, EMBO J, https://doi.org/10.1038/s44318-024-00036-1; Nguyen et al., 2023, Mol Cell/bioRxiv record, https://doi.org/10.1101/2022.08.14.503930; Schmid et al., 2024, Front Immunol, https://doi.org/10.3389/fimmu.2024.1356369 (pqac-00000002, pqac-00000006) |
| Focal-adhesion / cytoskeletal signaling | Recent work identifies TBK1 as a regulator of actin-adhesion remodeling through Zyxin, linking innate immune sensing to cell motility and tissue positioning (pqac-00000011, pqac-00000015) | STING or MAVS signalosomes activate TBK1, which drives Zyxin phosphorylation at S142/S143; phospho-Zyxin colocalizes with TBK1 puncta and focal adhesions, promoting focal-adhesion/F-actin reorganization and reducing macrophage migration (pqac-00000011, pqac-00000015) | Zyxin; upstream STING/MAVS signalosomes; downstream F-actin/focal-adhesion machinery; TBK1 inhibitors BX795 and MRT67307 suppress Zyxin phosphorylation together with IRF3 phosphorylation (pqac-00000011, pqac-00000015) | STING aggregates/signalosomes, TBK1 puncta, focal adhesions, macrophage cytoplasm (pqac-00000011, pqac-00000015) | Zhou et al., 2024, EMBO J, https://doi.org/10.1038/s44318-024-00244-9 (pqac-00000011, pqac-00000015) |
| Upstream activation by PTK2B | PTK2B/PYK2 is an upstream tyrosine kinase that enhances TBK1 activation in antiviral signaling by promoting TBK1 oligomerization (pqac-00000010) | PTK2B directly phosphorylates TBK1 at Tyr591 in the scaffold/dimerization domain, increasing TBK1 oligomerization and activation; PTK2B also promotes STING oligomerization through a kinase-independent mechanism, strengthening STING–TBK1 signaling (pqac-00000010) | PTK2B, TBK1 Y591, STING, IRF3; PTK2B deficiency reduces antiviral signaling and increases susceptibility to viral infection in mouse models (pqac-00000010) | Golgi-associated granules/signalosomes containing STING and TBK1 during infection; immune-cell cytoplasm (pqac-00000010) | Lin et al., 2023, Nat Commun, https://doi.org/10.1038/s41467-023-43419-4 (pqac-00000010) |
| Cancer context | TBK1 is frequently positioned as a multifunctional cancer-cell survival and tumor-immune regulator, especially in KRAS-driven and inflammatory tumor contexts; its effects can be tumor-promoting or context-dependent via IFN-I pathways (pqac-00000003, pqac-00000004, pqac-00000007) | Oncogenic inputs such as KRAS→RalB/Sec5 and growth-factor→TBK1–TBKBP1–CARD10–PKCθ pathways increase TBK1 activation (including S172 and S716-linked regulation), supporting NF-κB/IFN signaling, anti-apoptotic transcription, autophagy, and tumor–microenvironment crosstalk (pqac-00000003, pqac-00000007) | RalB, Sec5, PKCθ, TBKBP1, CARD10, NEMO, IRF3, NF-κB components including c-Rel and BCL-xL-linked outputs; additional reported substrates include Sec5, p62, and OPTN (pqac-00000003, pqac-00000004) | Cytosol and signalosome-associated compartments; Golgi-associated pre-autophagosome initiation sites; tumor and immune-cell compartments (pqac-00000003, pqac-00000004) | Hu & Zhang, 2024, Cell Insight, https://doi.org/10.1016/j.cellin.2024.100197; Miranda et al., 2024, Trends Cancer, https://doi.org/10.1016/j.trecan.2024.02.007; Wang et al., 2024, Front Immunol, https://doi.org/10.3389/fimmu.2024.1433321 (pqac-00000003, pqac-00000004) |


*Table: This table summarizes the major functional areas of human TBK1 (UniProt Q9UHD2), including its core mechanisms, substrates, localization, and recent representative sources. It is useful as a compact reference for innate immunity, autophagy, cytoskeletal signaling, upstream activation, and cancer-related roles.*