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

Justin Taft; Michael Markson; Diana Legarda; Roosheel Patel; Mark Chan; Louise Malle; Ashley Richardson; Conor Gruber; Marta Martín-Fernández; Grazia M.S. Mancini; Jan A.M. van Laar; Philomine van Pelt; Sofija Buta; Beatrijs H.A. Wokke; Ira K.D. Sabli; Vanessa Sancho-Shimizu; Pallavi Pimpale Chavan; Oskar Schnappauf; Raju Khubchandani; Müşerref Kasap Cüceoğlu; Seza Özen; Daniel L. Kastner; Adrian T. Ting; Ivona Aksentijevich; Iris H.I.M. Hollink; Dusan Bogunovic

doi:10.1016/j.cell.2021.07.026

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

Justin Taft, Michael Markson, Diana Legarda, Roosheel Patel, Mark Chan, Louise Malle, Ashley Richardson, Conor Gruber, Marta Martín-Fernández, Grazia M.S. Mancini, Jan A.M. van Laar, Philomine van Pelt, Sofija Buta, Beatrijs H.A. Wokke, Ira K.D. Sabli, Vanessa Sancho-Shimizu, Pallavi Pimpale Chavan, Oskar Schnappauf, Raju Khubchandani, Müşerref Kasap CüceoğluSeza Özen, Daniel L. Kastner, Adrian T. Ting, Ivona Aksentijevich, Iris H.I.M. Hollink, Dusan Bogunovic

Immunology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	4447-4463.e20
Journal	Cell
Volume	184
Issue number	17
DOIs	https://doi.org/10.1016/j.cell.2021.07.026
State	Published - Aug 19 2021

Keywords

IKKE
IRF3
RIPK1
TBK1 deficiency
TNF alpha
autoinflammation
interferon type I
viral susceptibility

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2021.07.026

Cite this

Taft, J., Markson, M., Legarda, D., Patel, R., Chan, M., Malle, L., Richardson, A., Gruber, C., Martín-Fernández, M., Mancini, G. M. S., van Laar, J. A. M., van Pelt, P., Buta, S., Wokke, B. H. A., Sabli, I. K. D., Sancho-Shimizu, V., Chavan, P. P., Schnappauf, O., Khubchandani, R., ... Bogunovic, D. (2021). Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell, 184(17), 4447-4463.e20. https://doi.org/10.1016/j.cell.2021.07.026

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 2021, 'Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death', Cell, vol. 184, no. 17, pp. 4447-4463.e20. https://doi.org/10.1016/j.cell.2021.07.026

@article{a64683e377c843a58375504067538833,

title = "Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death",

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",

author = "Justin Taft and Michael Markson and Diana Legarda and Roosheel Patel and Mark Chan and Louise Malle and Ashley Richardson and Conor Gruber and Marta Mart{\'i}n-Fern{\'a}ndez and Mancini, {Grazia M.S.} and {van Laar}, {Jan A.M.} and {van Pelt}, Philomine and Sofija Buta and Wokke, {Beatrijs H.A.} and Sabli, {Ira K.D.} and Vanessa Sancho-Shimizu and Chavan, {Pallavi Pimpale} and Oskar Schnappauf and Raju Khubchandani and C{\"u}ceoğlu, {M{\"u}{\c s}erref Kasap} and Seza {\"O}zen and Kastner, {Daniel L.} and Ting, {Adrian T.} and Ivona Aksentijevich and Hollink, {Iris H.I.M.} and Dusan Bogunovic",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = aug,

day = "19",

doi = "10.1016/j.cell.2021.07.026",

language = "English (US)",

volume = "184",

pages = "4447--4463.e20",

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number = "17",

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TY - JOUR

T1 - Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death

AU - Taft, Justin

AU - Markson, Michael

AU - Legarda, Diana

AU - Patel, Roosheel

AU - Chan, Mark

AU - Malle, Louise

AU - Richardson, Ashley

AU - Gruber, Conor

AU - Martín-Fernández, Marta

AU - Mancini, Grazia M.S.

AU - van Laar, Jan A.M.

AU - van Pelt, Philomine

AU - Buta, Sofija

AU - Wokke, Beatrijs H.A.

AU - Sabli, Ira K.D.

AU - Sancho-Shimizu, Vanessa

AU - Chavan, Pallavi Pimpale

AU - Schnappauf, Oskar

AU - Khubchandani, Raju

AU - Cüceoğlu, Müşerref Kasap

AU - Özen, Seza

AU - Kastner, Daniel L.

AU - Ting, Adrian T.

AU - Aksentijevich, Ivona

AU - Hollink, Iris H.I.M.

AU - Bogunovic, Dusan

PY - 2021/8/19

Y1 - 2021/8/19

N2 - 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.

AB - 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.

KW - IKKE

KW - IRF3

KW - RIPK1

KW - TBK1 deficiency

KW - TNF alpha

KW - autoinflammation

KW - interferon type I

KW - viral susceptibility

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UR - http://www.scopus.com/inward/citedby.url?scp=85112763794&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.07.026

DO - 10.1016/j.cell.2021.07.026

M3 - Article

C2 - 34363755

AN - SCOPUS:85112763794

SN - 0092-8674

VL - 184

SP - 4447-4463.e20

JO - Cell

JF - Cell

IS - 17

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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