Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death.
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
/ enzymology
Interferon Type I
/ metabolism
Interferon-gamma
/ metabolism
Loss of Function Mutation
/ genetics
Male
Pedigree
Phosphorylation
/ drug effects
Protein Serine-Threonine Kinases
/ deficiency
Receptor-Interacting Protein Serine-Threonine Kinases
/ metabolism
Receptors, Pattern Recognition
/ metabolism
Toll-Like Receptor 3
/ metabolism
Transcriptome
/ genetics
Tumor Necrosis Factor-alpha
/ pharmacology
Vesiculovirus
/ drug effects
IKKE
IRF3
RIPK1
TBK1 deficiency
TNF alpha
autoinflammation
interferon type I
viral susceptibility
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
19 08 2021
19 08 2021
Historique:
received:
23
12
2020
revised:
11
05
2021
accepted:
20
07
2021
pubmed:
8
8
2021
medline:
6
1
2022
entrez:
7
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34363755
pii: S0092-8674(21)00885-0
doi: 10.1016/j.cell.2021.07.026
pmc: PMC8380741
mid: NIHMS1727837
pii:
doi:
Substances chimiques
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
0
Interferon-gamma
82115-62-6
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 2.7.11.1
I-kappa B Kinase
EC 2.7.11.10
CYLD protein, human
EC 3.4.19.12
Deubiquitinating Enzyme CYLD
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4447-4463.e20Subventions
Organisme : NIAID NIH HHS
ID : R01 AI127372
Pays : United States
Organisme : NIAID NIH HHS
ID : F31 AI138363
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007647
Pays : United States
Organisme : Medical Research Council
ID : MR/S032304/1
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI151029
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI052417
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI148963
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests D.B. is the founder of Lab11 Therapeutics.
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