Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death
Open accessAbstract
TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Loss of TBK1 signaling is not associated with sepsis or increased incidence/severity of viral illnesses.
“but not sepsis or increased incidence/severity of viral illnesses 49”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [49]
The Results section says the four TBK1-deficient patients appeared to have adequate antiviral protection, and the Discussion reports no overt viral sensitivity in those patients. Our copy does not address sepsis, and its finding in four patients does not establish that loss of TBK1 signaling generally has no association with increased viral illness incidence or severity. The paper also notes herpes simplex encephalitis in people with different TBK1 mutations. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLoss of TBK1 signaling is associated with a milder TNF-driven autoinflammatory syndrome.
“observations from patients with inherited TBK1 deficiency suggests that loss of TBK1 signaling is associated with a milder TNFdriven autoinflammatory syndrome”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [49]
The Discussion describes TBK1 deficiency as causing chronic, systemic autoinflammation driven by an imbalance in TNF signaling. The Results describe substantial symptoms in the four patients, but the paper does not characterize the syndrome as milder or establish a severity comparison. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTBK1 has an emerging role in regulating death receptor signaling distinct from its role in innate immune response and viral sensing.
“However, TBK1 has an emerging role in regulating death receptor signaling distinct from its role in innate immune response and viral sensing 35,36,49 .”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [49]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 82 · Cited by 151
- Authors
- Taft, J., Markson, M., Legarda, D., Patel, R., Chan, M., Malle, L., Richardson, A., Gruber, C., Martín-Fernández, M., Mancini, G. M. S., van Laar, J. A. M., van Pelt, P., Buta, S., Wokke, B. H. A., Sabli, I. K. D., Sancho-Shimizu, V., Chavan, P. P., Schnappauf, O., Khubchandani, R., Cüceoğlu, M. K., Özen, S., Kastner, D. L., Ting, A. T., Aksentijevich, I., Hollink, I. H. I. M., & Bogunovic, D.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Mayo Clinic (US)
- Erasmus MC (NL)
- Imperial College London (GB)
- National Human Genome Research Institute (US)
- Breach Candy Hospital (IN)
- Hacettepe University (TR)
- Corresponding author
- Bogunovic, Dusan
- ORCID
- Taft, Justin
- Markson, Michael
- Legarda, Diana
- Patel, Roosheel
- Chan, Mark
- Malle, Louise
- Richardson, Ashley
- Gruber, Conor
- Martín-Fernández, Marta
- Mancini, Grazia M.S.
- Buta, Sofija
- Wokke, Beatrijs H.A.
- Sabli, Ira K.D.
- Chavan, Pallavi Pimpale
- Schnappauf, Oskar
- Khubchandani, Raju
- Cüceoğlu, Müşerref Kasap
- Özen, Seza
- Kastner, Daniel L.
- Ting, Adrian T.
- Aksentijevich, Ivona
- Hollink, Iris H.I. M.
- Bogunovic, Dusan
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 184
- Issue
- 17
- Pages
- 4447-4463.e20
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8380741
- OpenAlex
- W3190205340
- Cited by
- 151
- References
- 82
- Citations by year
- 2026: 27 · 2025: 30 · 2024: 36 · 2023: 31 · 2022: 25 · 2021: 2
- FWCI
- 8.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 384 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Publication Server of Bonn-Rhein-Sieg University of Applied Sciences (Bonn-Rhein-Sieg University of Applied Sciences) (submittedVersion)
- Funders
- NIAID (T32 AI007647, F31 AI138363, R01 AI151029, R01 AI148963, R01 AI127372)
- TÜBİTAK (315S096)
- NIH (AI126036, AI052417)
- UK Research and Innovation (T32 AI007647, F31 AI138363, MR/S032304/1)
- National Human Genome Research Institute
- Icahn School of Medicine at Mount Sinai
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TBK1, autoinflammation, necroptosis, TNF-α, NF-κB, interleukin-6, consanguineous family, loss-of-function mutations, anti-TNF therapy, cleaved caspase-3, genetic disorders
- MeSH terms
- A549 Cells, Loss of Function Mutation, Deubiquitinating Enzyme CYLD, Brain, Female, Homozygote, Humans, Inflammation, Interferon Type I, Interferon-gamma, Male, Pedigree, Phosphorylation, Tumor Necrosis Factor-alpha, Autoimmunity, Immunophenotyping, Cytokines, Cell Death, Apoptosis, Protein Serine-Threonine Kinases, Vesiculovirus, Adaptor Proteins, Signal Transducing, Receptors, Pattern Recognition, Toll-Like Receptor 3, I-kappa B Kinase, Receptor-Interacting Protein Serine-Threonine Kinases, HEK293 Cells, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
