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

被引：89

作者：

Taft, Justin ^{[1
,2
,3
,4
,5
]}

Markson, Michael ^{[1
,2
,3
,4
,5
]}

Legarda, Diana ^{[2
]}

Patel, Roosheel ^{[1
,2
,3
,4
,5
]}

Chan, Mark ^{[6
]}

Malle, Louise ^{[1
,2
,3
,4
,5
]}

Richardson, Ashley ^{[1
,2
,3
,4
,5
]}

Gruber, Conor ^{[1
,2
,3
,4
,5
]}

Martin-Fernandez, Marta ^{[1
,2
,3
,4
,5
]}

Mancini, Grazia M. S. ^{[7
]}

van Laar, Jan A. M. ^{[8
]}

van Pelt, Philomine ^{[9
]}

Buta, Sofija ^{[1
,2
,3
,4
,5
]}

Wokke, Beatrijs H. A. ^{[10
]}

Sabli, Ira K. D. ^{[11
,12
]}

Sancho-Shimizu, Vanessa ^{[11
,12
]}

Chavan, Pallavi Pimpale ^{[13
,14
]}

Schnappauf, Oskar ^{[13
]}

Khubchandani, Raju ^{[14
,15
]}

Cuceoglu, Muserref Kasap ^{[16
]}

Ozen, Seza ^{[16
]}

Kastner, Daniel L. ^{[13
]}

Ting, Adrian T. ^{[6
]}

Aksentijevich, Ivona ^{[13
]}

Hollink, Iris H. I. M. ^{[7
]}

Bogunovic, Dusan ^{[1
,2
,3
,4
,5
]}

机构：

[1] Icahn Sch Med Mt Sinai, Ctr Inborn Errors Immun, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Precis Immunol Inst, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA

[5] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA

[6] Mayo Clin, Dept Immunol, Rochester, MN 55905 USA

[7] Erasmus MC, Dept Clin Genet, NL-3015 GD Rotterdam, Netherlands

[8] Erasmus MC, Dept Immunol, NL-3015 GD Rotterdam, Netherlands

[9] Erasmus MC, Dept Rheumatol, NL-3015 GD Rotterdam, Netherlands

[10] Erasmus MC, Dept Neurol, NL-3015 GD Rotterdam, Netherlands

[11] Imperial Coll London, Dept Paediat Infect Dis & Virol, London, England

[12] Imperial Coll London, Fac Med, Ctr Paediat & Child Hlth, London, England

[13] NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA

[14] SRCC Childrens Hosp, Pediat Rheumatol, Mumbai, Maharashtra, India

[15] Jaslok & Breach Candy Hosp, Mumbai, Maharashtra, India

[16] Hacettepe Univ, Dept Pediat Rheumatol, Ankara, Turkey

来源：

CELL | 2021年 / 184卷 / 17期

关键词：

NF-KAPPA-B; TUMOR-SUPPRESSOR CYLD; IKK-EPSILON; DEUBIQUITINATING ENZYME; ACTIVATION; MUTATIONS; APOPTOSIS; UBIQUITIN; PHOSPHORYLATION; AUTOPHAGY;

D O I：

10.1016/j.cell.2021.07.026

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

TANK binding kinase 1 (TBK1) regulates IFN-I, NF-kappa B, 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-kappa B. 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.

引用

页码：4447 / +

页数：37

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