Functional Dissection of the TBK1 Molecular Network
Open accessAbstract
TANK-binding kinase 1 (TBK1) and inducible IκB-kinase (IKK-i) are central regulators of type-I interferon induction. They are associated with three adaptor proteins called TANK, Sintbad (or TBKBP1) and NAP1 (or TBKBP2, AZI2) whose functional relationship to TBK1 and IKK-i is poorly understood. We performed a systematic affinity purification-mass spectrometry approach to derive a comprehensive TBK1/IKK-i molecular network. The most salient feature of the network is the mutual exclusive interaction of the adaptors with the kinases, suggesting distinct alternative complexes. Immunofluorescence data indicated that the individual adaptors reside in different subcellular locations. TANK, Sintbad and NAP1 competed for binding of TBK1. The binding site for all three adaptors was mapped to the C-terminal coiled-coil 2 region of TBK1. Point mutants that affect binding of individual adaptors were used to reconstitute TBK1/IKK-i-deficient cells and dissect the functional relevance of the individual kinase-adaptor edges within the network. Using a microarray-derived gene expression signature of TBK1 in response virus infection or poly(I∶C) stimulation, we found that TBK1 activation was strictly dependent on the integrity of the TBK1/TANK interaction.
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Whether TBK1 acts on autophagy or innate immunity may partially depend on its associations with specific adaptor proteins such as NAP1L1, TANK and TBKBP1/SINTBAD that bind in a mutually exclusive manner.
“Whether TBK1 acts on autophagy or innate immunity may partially depend on its associations with specific adaptor proteins such as NAP1L1 (nucleosome assembly protein 1), TANK and TBKBP1/SINTBAD that bind in a mutually exclusive manner [58,200,201].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [200]
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- Authors
- Goncalves, A., Bürckstümmer, T., Dixit, E., Scheicher, R., Górna, M. W., Karayel, E., Sugar, C., Stukalov, A., Berg, T., Kralovics, R., Planyavsky, M., Bennett, K. L., Colinge, J., & Superti-Furga, G.
- Affiliations
- Austrian Academy of Sciences (AT)
- Corresponding author
- Bürckstümmer, Tilmann
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-09-08
- Volume
- 6
- Issue
- 9
- Pages
- e23971
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3169550
- OpenAlex
- W2095249521
- Cited by
- 136
- References
- 46
- Citations by year
- 2026: 10 · 2025: 4 · 2024: 10 · 2023: 9 · 2022: 8 · 2021: 12 · 2020: 12 · 2019: 4 · 2018: 11 · 2017: 5 · 2016: 12 · 2015: 12 · 2014: 10 · 2013: 14 · 2012: 3
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Université de Lausanne
- FP7 Ideas: European Research Council (250179)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TBK1, tanks, NAP1, type I interferon induction, poly(I:C) stimulation, gene expression signatures
- MeSH terms
- Amino Acid Sequence, Animals, HeLa Cells, Humans, Molecular Sequence Data, Proteins, tRNA Methyltransferases, Protein Serine-Threonine Kinases, Protein Structure, Secondary, Protein Transport, Protein Interaction Mapping, Intracellular Space, Adaptor Proteins, Signal Transducing, Mice, I-kappa B Kinase
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