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

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

doi:10.1016/j.cell.2021.07.026

Cited by 74 publications

(61 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, TBK1 has been shown to play a critical role in the prevention of inflammation by suppressing TNFα-RIPK1-mediated cell death. Consistent with these studies in animal models, recently, homozygous point mutations of TBK1 (including W619X, Y212D, and R440X) were detected in 4 patients with an unidentified chronic, systemic autoimmune syndrome [ 189 ]. All these mutations are loss-of-function mutations.…”

Section: Introductionmentioning

confidence: 56%

“…Consequently, all four patients presented with normal antiviral immune function. The autoimmune symptoms which developed in these patients might be associated with over-activation of TNFα signaling because they could be ameliorated by anti-TNFα therapy [ 189 ]. Such a clinical observation is consistent with the laboratory findings in animal models that TBK1 restrains TNF-induced RIPK1-MLKL activation [ 74 , 145 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The role of TBK1 in cancer pathogenesis and anticancer immunity

Runde

Mack

et al. 2022

J Exp Clin Cancer Res

View full text Add to dashboard Cite

The TANK-binding kinase 1 (TBK1) is a serine/threonine kinase belonging to the non-canonical inhibitor of nuclear factor-κB (IκB) kinase (IKK) family. TBK1 can be activated by pathogen-associated molecular patterns (PAMPs), inflammatory cytokines, and oncogenic kinases, including activated K-RAS/N-RAS mutants. TBK1 primarily mediates IRF3/7 activation and NF-κB signaling to regulate inflammatory cytokine production and the activation of innate immunity. TBK1 is also involved in the regulation of several other cellular activities, including autophagy, mitochondrial metabolism, and cellular proliferation. Although TBK1 mutations have not been reported in human cancers, aberrant TBK1 activation has been implicated in the oncogenesis of several types of cancer, including leukemia and solid tumors with KRAS-activating mutations. As such, TBK1 has been proposed to be a feasible target for pharmacological treatment of these types of cancer. Studies suggest that TBK1 inhibition suppresses cancer development not only by directly suppressing the proliferation and survival of cancer cells but also by activating antitumor T-cell immunity. Several small molecule inhibitors of TBK1 have been identified and interrogated. However, to this point, only momelotinib (MMB)/CYT387 has been evaluated as a cancer therapy in clinical trials, while amlexanox (AMX) has been evaluated clinically for treatment of type II diabetes, nonalcoholic fatty liver disease, and obesity. In this review, we summarize advances in research into TBK1 signaling pathways and regulation, as well as recent studies on TBK1 in cancer pathogenesis. We also discuss the potential molecular mechanisms of targeting TBK1 for cancer treatment. We hope that our effort can help to stimulate the development of novel strategies for targeting TBK1 signaling in future approaches to cancer therapy.

show abstract

Section: Introductionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

The role of TBK1 in cancer pathogenesis and anticancer immunity

Runde

Mack

et al. 2022

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…These results raise the possibility of using TBK1/IKKε inhibitors therapeutically to attenuate eTLR-driven pathogenic inflammatory responses and cytokine storm, as may occur in RA or COVID-19. This therapeutic strategy would need to be pursued cautiously in primarily TNF-driven diseases or subsets of RA patients, given that TBK1 also restrains RIPK1 and associated cell death 73,74,75 .…”

Section: Discussionmentioning

confidence: 99%

Costimulation of TLR8 responses by CXCL4 in Human Monocytes Mediated by TBK1-IRF5 Signaling and Epigenomic Remodeling

Bachu

Brauner

et al. 2022

Preprint

View full text Add to dashboard Cite

Regulation of endosomal TLR responses by the chemokine CXCL4 is implicated in inflammatory and fibrotic diseases. The current paradigm is that CXCL4 potentiates TLR responses by binding and facilitating endosomal delivery of nucleic acid TLR ligands. We report that in human monocytes/macrophages, CXCL4 initiates signaling cascades and downstream epigenomic reprogramming that change the profile of the TLR8 response by selectively and dramatically amplifying inflammatory gene transcription and IL-1beta; production, while partially attenuating the IFN response. Mechanistically, costimulation by CXCL4 and TLR8 synergistically activated TBK1/IKKε; and repurposed these kinases towards an inflammatory response via coupling with IRF5, and by activating the NLRP3 inflammasome without the need for an exogenous activator of a second signal for IL-1beta; maturation. CXCL4 signaling strongly induced chromatin remodeling and de novo enhancers associated with inflammatory genes in a cooperative and synergistic manner with TLR8. These findings identify new mechanisms of regulation of TLR responses relevant for cytokine storm, and suggest targeting the TBK1/IKKε;-IRF5 axis may be beneficial in inflammatory diseases.

show abstract

“…LUBAC prevents cell death in response to TRAIL, FAS, TLR and TNF signalling, and A20, in addition to its inhibitory role in TNF-dependent inflammation, is implicated in dysregulation of cell death 86 . Another deubiquitylase, CYLD, has a role in an autoinflammatory disease that is caused by deficiency of TANK binding kinase 1 (TBK1) 154 . Although TBK1 is known to regulate the type I interferon pathway, TBK1-deficient individuals maintain hypomorphic but sufficient interferon induction via the RIG-I–MAVS pathway, and present with severe systemic inflammation resulting from dysregulation of TNF-induced RIPK1-mediated cell death 154 .…”

Section: Stress and Cell Death In Immune Cellsmentioning

confidence: 99%

“…Another deubiquitylase, CYLD, has a role in an autoinflammatory disease that is caused by deficiency of TANK binding kinase 1 (TBK1) 154 . Although TBK1 is known to regulate the type I interferon pathway, TBK1-deficient individuals maintain hypomorphic but sufficient interferon induction via the RIG-I–MAVS pathway, and present with severe systemic inflammation resulting from dysregulation of TNF-induced RIPK1-mediated cell death 154 . Fibroblasts derived from patients with TBK1 deficiency display heightened sensitivity to necroptosis that results from the lack of inhibitory phosphorylation on CYLD, which increases its deubiquitylation activity towards RIPK1.…”

Section: Stress and Cell Death In Immune Cellsmentioning

confidence: 99%

Disorders of ubiquitylation: unchained inflammation

et al. 2022

Self Cite

View full text Add to dashboard Cite

Ubiquitylation is an essential post-translational modification that regulates intracellular signalling networks by triggering proteasomal substrate degradation, changing the activity of substrates or mediating changes in proteins that interact with substrates. Hundreds of enzymes participate in reversible ubiquitylation of proteins, some acting globally and others targeting specific proteins. Ubiquitylation is essential for innate immune responses, as it facilitates rapid regulation of inflammatory pathways, thereby ensuring sufficient but not excessive responses. A growing number of inborn errors of immunity are attributed to dysregulated ubiquitylation. These genetic disorders exhibit broad clinical manifestations, ranging from susceptibility to infection to autoinflammatory and/or autoimmune features, lymphoproliferation and propensity to malignancy. Many autoinflammatory disorders result from disruption of components of the ubiquitylation machinery and lead to overactivation of innate immune cells. An understanding of the disorders of ubiquitylation in autoinflammatory diseases could enable the development of novel management strategies.

show abstract

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

Cited by 74 publications

References 77 publications

The role of TBK1 in cancer pathogenesis and anticancer immunity

The role of TBK1 in cancer pathogenesis and anticancer immunity

Costimulation of TLR8 responses by CXCL4 in Human Monocytes Mediated by TBK1-IRF5 Signaling and Epigenomic Remodeling

Disorders of ubiquitylation: unchained inflammation

Contact Info

Product

Resources

About