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
N1 - Funding Information:
We thank the patients and their families for their participation in this study. We thank Adeeb Rahman, Brian Lee, Daniel Geanon, Geoffrey Kelly, Kevin Tuballes, and Laura Walker from the Mount Sinai Human Immune Monitoring Center for their help designing and performing the CyTOF and scRNAseq experiments. We thank Dr. Frans Verheijen of the Department of Clinical Genetics at Erasmus MC and Dr. Rik Brooimans of the Erasmus MC Laboratory of Medical Immunology for their assistance. The graphical abstract was created with BioRender. This research was supported by NIAID grants R01 AI127372 , R01 AI148963 , and R01 AI151029 as well as the Hirschl Scholar Award to D.B. A.T. was funded by NIH grants AI052417 and AI126036 . S.O. was funded by INSAID project E-rare 2015, 15-pp-156, and TÜBİTAK project 315S096. V.S.-S. was funded by UKRI grant MR/S032304/1. J.T. was funded by NIAID grants F31 AI138363 and T32 AI007647 . This work was also supported by the Intramural Research Programs of the National Human Genome Research Institute, Bethesda, Maryland.
Funding Information:
We thank the patients and their families for their participation in this study. We thank Adeeb Rahman, Brian Lee, Daniel Geanon, Geoffrey Kelly, Kevin Tuballes, and Laura Walker from the Mount Sinai Human Immune Monitoring Center for their help designing and performing the CyTOF and scRNAseq experiments. We thank Dr. Frans Verheijen of the Department of Clinical Genetics at Erasmus MC and Dr. Rik Brooimans of the Erasmus MC Laboratory of Medical Immunology for their assistance. The graphical abstract was created with BioRender. This research was supported by NIAID grants R01 AI127372, R01 AI148963, and R01 AI151029 as well as the Hirschl Scholar Award to D.B. A.T. was funded by NIH grants AI052417 and AI126036. S.O. was funded by INSAID project E-rare 2015, 15-pp-156, and T?B?TAK project 315S096. V.S.-S. was funded by UKRI grant MR/S032304/1. J.T. was funded by NIAID grants F31 AI138363 and T32 AI007647. This work was also supported by the Intramural Research Programs of the National Human Genome Research Institute, Bethesda, Maryland. J.T. designed and performed most of the experiments, analyzed the data, and wrote the manuscript. M.M. performed multiple experiments and generated and maintained cell lines. D.L. designed and performed all experiments in Figure 4. R.P. analyzed the scRNA-seq and edited the manuscript. M.C. performed many optimization experiments and generated the data in Figure S5E. L.M. ran Luminex and edited the manuscript. A.R. helped perform experiments. C.G. ran Luminex and the autoantibodies array. M.M.-F. ran the autoantibodies array and edited the manuscript. S.B. performed experiments and maintained and generated cell lines. G.M.S.M. J.A.M.v.L. P.v.P. and B.H.A.W. are P1 and P2?s physicians and helped edit the manuscript. I.K.D.S. and V.S.-S. performed LC3 microscopy. P.P.C. is P3?s physician and coordinated P3 sample collection and shipment. O.S. analyzed P3 WES. R.K. is P3?s physician. M.K.C. and S.O. are P4?s physicians. D.K. helped conceptualize the work. A.T.T. helped conceptualize the work, designed and supervised all experiments in Figure 4, and helped design cell death experiments. I.A. helped conceptualize the work and edited the manuscript. I.H.I.M.H. helped conceptualize the work, helped edit the manuscript, and analyzed P1 and P2 WES. D.B. supervised the work, wrote the manuscript, and helped design the experiments and analyze the data. D.B. is the founder of Lab11 Therapeutics. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure that the study questionnaires were prepared in an inclusive way. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.
Publisher Copyright:
© 2021 Elsevier Inc.
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
UR - http://www.scopus.com/inward/record.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 -