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.
Keywords:
IKKE; IRF3; RIPK1; TBK1 deficiency; TNF alpha; autoinflammation; interferon type I; viral susceptibility.
Copyright © 2021 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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A549 Cells
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Adaptor Proteins, Signal Transducing / metabolism
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Apoptosis
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Autoimmunity / drug effects
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Brain / diagnostic imaging
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Cell Death / drug effects
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Cytokines / metabolism
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Deubiquitinating Enzyme CYLD / metabolism
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Female
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HEK293 Cells
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Homozygote
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Humans
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I-kappa B Kinase / metabolism
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Immunophenotyping
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Inflammation / enzymology*
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Inflammation / pathology
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Interferon Type I / metabolism
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Interferon-gamma / metabolism
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Loss of Function Mutation / genetics
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Male
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Pedigree
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / deficiency*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
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Receptors, Pattern Recognition / metabolism
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Toll-Like Receptor 3 / metabolism
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Transcriptome / genetics
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Tumor Necrosis Factor-alpha / pharmacology*
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Vesiculovirus / drug effects
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Vesiculovirus / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Cytokines
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Interferon Type I
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MAVS protein, human
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Receptors, Pattern Recognition
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Toll-Like Receptor 3
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Tumor Necrosis Factor-alpha
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Interferon-gamma
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Protein Serine-Threonine Kinases
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RIPK1 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinases
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TBK1 protein, human
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I-kappa B Kinase
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CYLD protein, human
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Deubiquitinating Enzyme CYLD