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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.

Competing Interests: Declaration of interests D.B. is the founder of Lab11 Therapeutics.

Titel:	Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death.
Autor/in / Beteiligte Person:	Taft, J ; Markson, M ; Legarda, D ; Patel, R ; Chan, M ; Malle, L ; Richardson, A ; Gruber, C ; Martín-Fernández, M ; Mancini, GMS ; van Laar JAM ; van Pelt P ; Buta, S ; Wokke, BHA ; Sabli, IKD ; Sancho-Shimizu, V ; Chavan, PP ; Schnappauf, O ; Khubchandani, R ; Cüceoğlu, MK ; Özen, S ; Kastner, DL ; Ting, AT ; Aksentijevich, I ; Hollink, IHIM ; Bogunovic, D
Link:	Zum Volltext
Zeitschrift:	Cell, Jg. 184 (2021-08-19), Heft 17, S. 4447
Veröffentlichung:	Cambridge, Ma : Cell Press ; <i>Original Publication</i>: Cambridge, MIT Press., 2021
Medientyp:	academicJournal
ISSN:	1097-4172 (electronic)
DOI:	10.1016/j.cell.2021.07.026
Schlagwort:	A549 Cells Adaptor Proteins, Signal Transducing metabolism Apoptosis Autoimmunity drug effects Brain diagnostic imaging Cell Death drug effects Cytokines metabolism Deubiquitinating Enzyme CYLD metabolism Female HEK293 Cells Homozygote Humans I-kappa B Kinase metabolism Immunophenotyping Inflammation pathology Interferon Type I metabolism Interferon-gamma metabolism Loss of Function Mutation genetics Male Pedigree Phosphorylation drug effects Protein Serine-Threonine Kinases genetics Protein Serine-Threonine Kinases metabolism Receptor-Interacting Protein Serine-Threonine Kinases metabolism Receptors, Pattern Recognition metabolism Toll-Like Receptor 3 metabolism Transcriptome genetics Vesiculovirus drug effects Vesiculovirus physiology Inflammation enzymology Protein Serine-Threonine Kinases deficiency Tumor Necrosis Factor-alpha pharmacology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Language: English [Cell] 2021 Aug 19; Vol. 184 (17), pp. 4447-4463.e20. <i>Date of Electronic Publication: </i>2021 Aug 06. MeSH Terms: Inflammation / enzymology ; Protein Serine-Threonine Kinases / deficiency ; Tumor Necrosis Factor-alpha / *pharmacology ; A549 Cells ; Adaptor Proteins, Signal Transducing / metabolism ; Apoptosis ; Autoimmunity / drug effects ; Brain / diagnostic imaging ; Cell Death / drug effects ; Cytokines / metabolism ; Deubiquitinating Enzyme CYLD / metabolism ; Female ; HEK293 Cells ; Homozygote ; Humans ; I-kappa B Kinase / metabolism ; Immunophenotyping ; Inflammation / pathology ; Interferon Type I / metabolism ; Interferon-gamma / metabolism ; Loss of Function Mutation / genetics ; Male ; Pedigree ; Phosphorylation / drug effects ; Protein Serine-Threonine Kinases / genetics ; Protein Serine-Threonine Kinases / metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases / metabolism ; Receptors, Pattern Recognition / metabolism ; Toll-Like Receptor 3 / metabolism ; Transcriptome / genetics ; Vesiculovirus / drug effects ; Vesiculovirus / physiology References: Trends Mol Med. 2016 Jun;22(6):511-527. 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(PMID: 24316671) Grant Information: R01 AI127372 United States AI NIAID NIH HHS; F31 AI138363 United States AI NIAID NIH HHS; T32 AI007647 United States AI NIAID NIH HHS; MR/S032304/1 United Kingdom MRC_ Medical Research Council; R01 AI151029 United States AI NIAID NIH HHS; R01 AI052417 United States AI NIAID NIH HHS; R01 AI148963 United States AI NIAID NIH HHS Contributed Indexing: Keywords: IKKE; IRF3; RIPK1; TBK1 deficiency; TNF alpha; autoinflammation; interferon type I; viral susceptibility Substance Nomenclature: 0 (Adaptor Proteins, Signal Transducing) ; 0 (Cytokines) ; 0 (Interferon Type I) ; 0 (MAVS protein, human) ; 0 (Receptors, Pattern Recognition) ; 0 (Toll-Like Receptor 3) ; 0 (Tumor Necrosis Factor-alpha) ; 82115-62-6 (Interferon-gamma) ; EC 2.7.11.1 (Protein Serine-Threonine Kinases) ; EC 2.7.11.1 (RIPK1 protein, human) ; EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases) ; EC 2.7.11.1 (TBK1 protein, human) ; EC 2.7.11.10 (I-kappa B Kinase) ; EC 3.4.19.12 (CYLD protein, human) ; EC 3.4.19.12 (Deubiquitinating Enzyme CYLD) Entry Date(s): Date Created: 20210807 Date Completed: 20220105 Latest Revision: 20220820 Update Code: 20240513 PubMed Central ID: PMC8380741

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Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death.