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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

62 Citations (Scopus)


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 languageEnglish
Pages (from-to)4447-+
Issue number17
Publication statusPublished - 19 Aug 2021

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