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Taft J, Markson M, Legarda D, et al. Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell. 2021;184(17):4447-4463.e20doi: 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, 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., Cüceoğlu, M. K., Özen, S., Kastner, D. L., Ting, A. T., Aksentijevich, I., Hollink, I. H. I. M., & 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, Justin, et al. "Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death." Cell vol. 184,17 (2021): 4447-4463.e20. doi: 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. Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell. 2021 Aug 19;184(17):4447-4463.e20. doi: 10.1016/j.cell.2021.07.026. Epub 2021 Aug 06. PMID: 34363755; PMCID: PMC8380741.
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Cell. 2021 Aug 19;184(17):4447-4463.e20. doi: 10.1016/j.cell.2021.07.026. Epub 2021 Aug 06.

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

Cell

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

Affiliations

  1. Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  2. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  3. Department of Immunology, Mayo Clinic, Rochester, MN, 55905, USA.
  4. Department of Clinical Genetics, Erasmus University Medical Center, 3015GD Rotterdam, the Netherlands.
  5. Department of Immunology, Erasmus University Medical Center, 3015GD Rotterdam, the Netherlands.
  6. Department of Rheumatology, Erasmus University Medical Center, 3015GD Rotterdam, the Netherlands.
  7. Department of Neurology, Erasmus University Medical Center, 3015GD Rotterdam, the Netherlands.
  8. Department of Paediatric Infectious Diseases and Virology, Imperial College London, London, UK; Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, UK.
  9. Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD, 20892, USA; Pediatric Rheumatology, SRCC Children's Hospital, Mumbai, India.
  10. Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
  11. Pediatric Rheumatology, SRCC Children's Hospital, Mumbai, India; Consultant Pediatrician, Jaslok and Breach Candy Hospitals, Mumbai, India.
  12. Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey.
  13. Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. Electronic address: [email protected].

PMID: 34363755 PMCID: PMC8380741 DOI: 10.1016/j.cell.2021.07.026

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.

Copyright © 2021 Elsevier Inc. All rights reserved.

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

Conflict of interest statement

Declaration of interests D.B. is the founder of Lab11 Therapeutics.

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