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

Taft J., Markson M., Legarda D., Patel R., Chan M., Malle L., ...More

Cell, vol.184, pp.4447-4483, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 184
  • Publication Date: 2021
  • Doi Number: 10.1016/j.cell.2021.07.026
  • Journal Name: Cell
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database, DIALNET
  • Page Numbers: pp.4447-4483
  • Hacettepe University Affiliated: Yes


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.