The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling
Open accessAbstract
Immunoglobulin class switching is crucial for the generation of antibody diversity in humoral immunity and, when deregulated, also has severe pathological consequences. How the magnitude of immunoglobulin isotype switching is controlled is still poorly understood. Here we identify the kinase TBK1 as a pivotal negative regulator of class switching to the immunoglobulin A (IgA) isotype. B cell-specific ablation of TBK1 in mice resulted in uncontrolled production of IgA and the development of nephropathy-like disease signs. TBK1 negatively regulated IgA class switching by attenuating noncanonical signaling via the transcription factor NF-κB, an action that involved TBK1-mediated phosphorylation and subsequent degradation of the NF-κB-inducing kinase NIK. Our findings establish TBK1 as a pivotal negative regulator of the noncanonical NF-κB pathway and identify a unique mechanism that controls IgA production.
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Recent studies have demonstrated critical roles for TBK1 and/or IKKε in regulation of activity of numerous immune cell types, including T cells, B cells, dendritic cells, and macrophages.
“Recent studies have demonstrated critical roles for TBK1 and/or IKK ε in regulation of activity of numerous immune cell types, including T cells 21 , B cells 22,23 , dendritic cells 24 , and macrophages 25,26 .”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [23]
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Self-citation
- Authors
- Jin, J., Xiao, Y., Chang, J.-H., Yu, J., Hu, H., Starr, R., Brittain, G. C., Chang, M., Cheng, X., & Sun, S.-C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- St Vincents Institute of Medical Research (AU)
- Corresponding author
- Sun, Shao-Cong
- Venue
- Nature Immunology
- Published
- 2012-09-30
- Volume
- 13
- Issue
- 11
- Pages
- 1101-1109
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3477307
- OpenAlex
- W2461505078
- Cited by
- 136
- References
- 53
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 8 · 2023: 10 · 2022: 15 · 2021: 12 · 2020: 12 · 2019: 12 · 2018: 15 · 2017: 7 · 2016: 6 · 2015: 10 · 2014: 5 · 2013: 8 · 2012: 2
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-07-03)
- Open access
- green
- europepmc.org
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Amgen
- National Cancer Institute (T32CA009598, P30CA016672)
- National Institute of General Medical Sciences (R01GM084459, GM084459)
- National Institute of Allergy and Infectious Diseases (AI064639, R01AI057555, R37AI064639, R01AI064639, AI057555)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TBK1, IgA class switching, non-canonical NF-κB signaling, NIK, B cells, humoral immunity, antibody isotype switching
- MeSH terms
- NF-kappaB-Inducing Kinase, Animals, B-Lymphocytes, Gene Expression Regulation, Glomerulonephritis, IGA, Immunoglobulin A, Phosphorylation, Signal Transduction, NF-kappa B, Protein Serine-Threonine Kinases, Gene Deletion, Immunoglobulin Class Switching, Mice, Knockout, Mice, Proteolysis
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