Identification of TBK1 complexes required for the phosphorylation of IRF3 and the production of interferon β

Bakshi, Siddharth; Taylor, Jordan S.; Strickson, Sam; McCartney, Thomas; Cohen, Philip

doi:10.1042/bcj20160992

Cited by 49 publications

(53 citation statements)

References 49 publications

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“…5C), suggesting that other unknown signaling molecules or feedback loops may also contribute to the regulation of different chemokines. LPS also has the ability to activate TBK1 to coordinate the activation of the IRF3 and NF-κB pathway in immune cells (39, 40). LDK378 also inhibited the LPS-induced phosphorylation of TBK1, IRF3, and p65 (fig.…”

Section: Resultsmentioning

confidence: 99%

ALK is a therapeutic target for lethal sepsis

et al. 2017

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Sepsis, a life-threatening organ dysfunction caused by infection, is a major public health concern with limited therapeutic options. We provide evidence to support a role for anaplastic lymphoma kinase (ALK), a tumor-associated receptor tyrosine kinase, in the regulation of innate immunity during lethal sepsis. The genetic disruption of ALK expression diminishes the stimulator of interferon genes (STING)–mediated host immune response to cyclic dinucleotides in monocytes and macrophages. Mechanistically, ALK directly interacts with epidermal growth factor receptor (EGFR) to trigger serine-threonine protein kinase AKT phosphorylation and activate interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) signaling pathways, enabling STING-dependent rigorous inflammatory responses. Moreover, pharmacological or genetic inhibition of the ALK-STING pathway confers protection against lethal endotoxemia and sepsis in mice. The ALK pathway is up-regulated in patients with sepsis. These findings uncover a key role for ALK in modulating the inflammatory signaling pathway and shed light on the development of ALK-targeting therapeutics for lethal systemic inflammatory disorders.

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Section: Resultsmentioning

confidence: 99%

ALK is a therapeutic target for lethal sepsis

et al. 2017

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“…3c). This prompted us to examine the levels of Tbk1, the protein that forms a complex with a variety of proteins ultimately resulting in activation of IRF3 31 , and Lgp2, a negative regulator of Rig1 32,33 . In keeping with the muted IRF3 response, we find that Tbk1 is downregulated and Lgp2 is robustly induced (4.2-fold) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Interferon mediated neuroinflammation in polyglutamine disease is not caused by RNA toxicity

2020

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Polyglutamine diseases are neurodegenerative diseases that occur due to the expansion of CAG repeat regions in coding sequences of genes. Previously, we have shown the formation of large protein aggregates along with activation of the interferon pathway leading to apoptosis in a cellular model of SCA17. Here, we corroborate our previous results in a tetracycline-inducible model of SCA17. Interferon gamma and lambda were upregulated in 59Q-TBP expressing cells as compared to 16Q-TBP expressing cells. Besides interferon-stimulated genes, the SCA17 model and Huntington's mice brain samples showed upregulation of RNA sensors. However, in this improved model interferon pathway activation and apoptosis preceded the formation of large polyglutamine aggregates, suggesting a role for CAG repeat RNA or soluble protein aggregates. A polyglutamine minus mutant of TBP, expressing polyCAG mRNA, was created by site directed mutagenesis of 10 potential start codons. Neither this long CAG embedded mRNA nor short polyCAG RNA could induce interferon pathway genes or cause apoptosis. polyQ-TBP induced the expression of canonical RNA sensors but the downstream transcription factor, IRF3, showed a muted response. We found that expanded CAG repeat RNA is not sufficient to account for the neuronal apoptosis. Neuronal cells sense expanded CAG repeats embedded in messenger RNAs of protein-coding genes. However, polyglutamine containing protein is responsible for the interferon-mediated neuroinflammation and cell death seen in polyglutamine disease. Thus, we delineate the inflammatory role of CAG repeats in the mRNA from the resulting polyglutamine tract in the protein. Embedded in messenger RNAs of protein-coding regions, the cell senses CAG repeat expansion and induces the expression of RNA sensors and interferon-stimulated genes.

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“…It has been reported that in the RLR signaling pathway, VISA/MAVS activates TBK1/IKKε via TRAFs proteins, and the combined deletion of TRAF completely abolishes the MAVS-TBK1/IKKε interaction and subsequent TBK1/IKKε activation [8,[10][11][12]. It was experimentally confirmed that MAVS recruits and activates TBK1/IKKε upon RNA virus infection through a preassociated TRAFs-TBK1/IKKε complex, resulting in activation of TBK1-IRF3 and type I IFN production [13].…”

Section: Introductionmentioning

confidence: 89%

ZWINT positively regulates TBK1-mediated RLR antiviral signaling

Li¹,

Xu²,

He³

et al. 2018

biomedicalresearch

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TANK-BindingKinase 1 (TBK1) is a serine/threonine kinase ubiquitously expressed in many tissues and plays an important role in the RLR antiviral signaling pathway. Upon viral infection, various virus components, including viral DNA, RNA are sensed by different pattern recognition receptors (PRRs). Among these PRRs, TLR3, RIG-I/MDA5, and cGAS recruit different adaptors including TRIF, VISA/ MAVS, and MITA/STING to activate TBK1. Activated TBK1 then promote the phosphorylation and homodimerization of IFN-regulatory factors 3 and 7 (IRF3/7), in turn promoting type-I Interferon (IFN-I) production. In this study, we reported that ZW10 Interacting Kinetochore Protein (ZWINT) positively regulates RLR antiviral signaling by targeting RIG-I/VISA/TBK1. Ectopic expression of ZWINT potentiated Sendai virus-induced, as well as TBK1-or VISA/MAVS-mediated IFN-β promoter activation by enhancing dimerization of IRF3. In contrast, knocking down of ZWINT expression with siRNA resulted in reduced IFN-β promoter activation and IRF3 dimerization induced by Sendai virus, indicating that ZWINT positively regulates TBK1-mediated RLR antiviral signaling.

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Identification of TBK1 complexes required for the phosphorylation of IRF3 and the production of interferon β

Cited by 49 publications

References 49 publications

ALK is a therapeutic target for lethal sepsis

ALK is a therapeutic target for lethal sepsis

Interferon mediated neuroinflammation in polyglutamine disease is not caused by RNA toxicity

ZWINT positively regulates TBK1-mediated RLR antiviral signaling

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