ArticleCell2021
Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death.
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Article in Cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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93citing papers in PubMed
7.9field-weighted citation impact, top 2% of its field
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Who cites it
93 citing papers in PubMed, 133 citations in OpenAlex.
- Death domain-mediated higher-order oligomerization of RIPK1 drives TNF-induced signaling.Cell death and differentiation · 2026Article
- Mechanisms, regulation and clinical relevance of necroptosis.Nature reviews. Molecular cell biology · 2026Review
- A Rare RIPK3 Variant Enhances Necroptosis and Promotes Inflammation in a Still Disease-Like Autoinflammatory Syndrome.Arthritis & rheumatology (Hoboken, N.J.) · 2026Article
- Convergent TBK1 loss of function drives gasdermin E dependent pyroptosis and motor neuron degeneration across ALS genotypes.Cell death and differentiation · 2026Article
- Clinical and immunological characterization of a child with a homozygous TBK1 kinase-domain truncation.Immunologic research · 2026Article
- Bridging the gap: neuroinflammation and the dawn of precision medicine in amyotrophic lateral sclerosis.Translational neurodegeneration · 2026Review
- Factors influencing preterm infant microbiota and their role in wheezing development.Pediatric research · 2026Article
- Single-cell RNA-sequencing reveals cellular heterogeneity and identifies biomarkers for obstructive sleep apnea and migraine.Human genomics · 2026Article
- Human ISG15 deficiency unveils impaired healing of ulcerations via type I interferon-mediated fibrosis.Journal of human immunity · 2026Article
- ADA2-deficient cells exhibit increased levels of cell death and metabolic disturbances.Cell death discovery · 2026Article
- CD8Nature communications · 2026Article
- Human TBK1 deficiency: An expanded spectrum from autoinflammation to viral encephalitis.Journal of human immunity · 2026Article
- Recurrent severe viral infection in a child with inherited complete TBK1 deficiency.Journal of human immunity · 2026Article
- Recent variant discoveries and emerging genetic mechanisms in autoinflammatory diseases.Frontiers in immunology · 2026Review
- Minding the gates: dual cell-autonomous and non-cell-autonomous mechanisms of TBK1 in ALS/FTD.Frontiers in neuroscience · 2026Review
- Monogenic disorders of the TNF signalling pathway.Nature reviews. Rheumatology · 2026Review
- AFrontiers in immunology · 2026Article
- Phospho-proteome profiling in human neurons reveals targets of TBK1 in ALS/FTD-associated autophagy networks.Cell reports · 2025Article
- Incomplete penetrance in inborn errors of immunity: A skeleton in the closet-The sequel.Journal of human immunity · 2025Review
- Inhibition of ARH2 by pH/ROS-responsive nanosystem for improved lung adenocarcinoma immunochemotherapy.Bioactive materials · 2025Article
33 more citing papers are in PubMed but not listed here.
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Authors and funding
26 authors at 8 institutions in 5 countries.
Justin TaftCenter for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Michael MarksonCenter for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Diana LegardaPrecision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Roosheel PatelCenter for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Mark ChanDepartment of Immunology, Mayo Clinic, Rochester, MN, 55905, USA.
Louise MalleCenter for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Ashley RichardsonCenter for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Conor GruberCenter for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Marta Martín-FernándezCenter for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Grazia M S ManciniDepartment of Clinical Genetics, Erasmus University Medical Center, 3015GD Rotterdam, the Netherlands.
Jan A M van LaarDepartment of Immunology, Erasmus University Medical Center, 3015GD Rotterdam, the Netherlands.
Philomine van PeltDepartment of Rheumatology, Erasmus University Medical Center, 3015GD Rotterdam, the Netherlands.
Sofija ButaCenter for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Beatrijs H A WokkeDepartment of Neurology, Erasmus University Medical Center, 3015GD Rotterdam, the Netherlands.
Ira K D SabliDepartment of Paediatric Infectious Diseases and Virology, Imperial College London, London, UK; Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, UK.
Vanessa Sancho-ShimizuDepartment of Paediatric Infectious Diseases and Virology, Imperial College London, London, UK; Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, UK.
Pallavi Pimpale ChavanInflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD, 20892, USA; Pediatric Rheumatology, SRCC Children's Hospital, Mumbai, India.
Oskar SchnappaufInflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Raju KhubchandaniPediatric Rheumatology, SRCC Children's Hospital, Mumbai, India; Consultant Pediatrician, Jaslok and Breach Candy Hospitals, Mumbai, India.
Müşerref Kasap CüceoğluDepartment of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
Seza ÖzenDepartment of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
Daniel L KastnerInflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Adrian T TingDepartment of Immunology, Mayo Clinic, Rochester, MN, 55905, USA.
Ivona AksentijevichInflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Iris H I M HollinkDepartment of Clinical Genetics, Erasmus University Medical Center, 3015GD Rotterdam, the Netherlands.
Dusan BogunovicCenter for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Electronic address: dusan.bogunovic@mssm.edu.
Child Health and Development Institute · USErasmus MC · NLNational Human Genome Research Institute · USHacettepe University · TRMayo Clinic · USNIHR Imperial Biomedical Research Centre · GBBreach Candy Hospital · INIcahn School of Medicine at Mount Sinai · US
Funding
Genetics, Pathophysiology, and Treatment of Recessive Autoinflammatory DiseasesZIAHG200372 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI KASTNER, DANIEL · 2011 to 2025
$27.2MTRAINING PROGRAM: MECHANISMS OF VIRUS-HOST INTERACTIONST32AI007647 · NIAID · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI Domenico Tortorella · 2000 to 2026
$11.5MRegulation of TNF Receptor-mediated Cell DeathR01AI052417 · NIAID · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI TING, ADRIAN T · 2002 to 2020
$5.9MHuman ISG15 and USP18 Deficiencies Underlying Type I InterferonopathiesR01AI127372 · NIAID · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Dusan Bogunovic · 2017 to 2026
$4.7MNext Generation Resolution of Antiviral Gene NetworksR01AI151029 · NIAID · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Dusan Bogunovic, Brad Rosenberg · 2020 to 2026
$4.2MInborn Errors of Immunity Leading to Autoinflammatory SyndromesR01AI148963 · NIAID · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI BOGUNOVIC, DUSAN · 2020 to 2024
$2.5MHost Genetic Control of ZIKV InfectionF31AI138363 · NIAID · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI TAFT, JUSTIN · 2019 to 2020
$91kMedical Research Council MR/S032304/1NIAID NIH HHS F31 AI138363NIAID NIH HHS R01 AI052417NIAID NIH HHS R01 AI127372NIAID NIH HHS R01 AI148963NIAID NIH HHS R01 AI151029NIAID NIH HHS T32 AI007647
Abstract
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.
Indexed as
A549 CellsAdaptor Proteins, Signal TransducingApoptosisAutoimmunityBrainCell DeathCytokinesDeubiquitinating Enzyme CYLDFemaleHEK293 CellsHomozygoteHumansI-kappa B KinaseImmunophenotypingInflammationInterferon-gammaAdaptor Proteins, Signal TransducingCYLD protein, humanCytokinesDeubiquitinating Enzyme CYLDI-kappa B KinaseInterferon-gammaInterferon Type IMAVS protein, humanProtein Serine-Threonine KinasesReceptor-Interacting Protein Serine-Threonine KinasesReceptors, Pattern RecognitionRIPK1 protein, humanTBK1 protein, humanToll-Like Receptor 3Tumor Necrosis Factor-alphaautoinflammationIKKEinterferon type IIRF3RIPK1TBK1 deficiencyTNF alphaviral susceptibility
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