Idronoxil inhibition of TBK1 signalling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA795919 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17522829_1.fastq.gz | Fastqsanger.gz | |||
| SRR17522829_2.fastq.gz | Fastqsanger.gz | |||
| SRR17522830_1.fastq.gz | Fastqsanger.gz | |||
| SRR17522830_2.fastq.gz | Fastqsanger.gz | |||
| SRR17522831_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Analysis of the transcriptional effects of Idronoxil (IDX) on primary bone marrow derived macrophages (BMDMs) from Trex1 mutant mice. Methods: Primary BMDMs from 3 different mice were treated overnight with Idronoxil at 1.25uM. RNA sequencing was performed with one NextSeq2000 P2 run using 19bp forward read and 101bp reverse reads. Conclusion: Idronoxil strongly decreased the basal TBK1 driven interferon gene signature in these cells.
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Project description:Outcomes in activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) remain poor and new targets for treatment are needed. NF-κB signalling pathways from the B-cell receptor and Toll-like receptors bear mutations and are constitutively active in ABC-DLBCL but inhibitors of the major components of these signalling pathways have not yet entered clinical practice. The IKK related kinases, IKKε/TBK1, have essential roles in innate immunity and regulate aspects of NF-κB signalling and other pathways. TBK1 mRNA expression is associated with clinical outcome and TBK1 and IKKε are variably expressed in human DLBCL.
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Project description:B-DNA-induced gene expression profile in wild-type, TBK1, IKKi(Ikbke), or TBK1 IKKi doubly deficient embryonic fibroblats; to elucidate how TBK1 and/or IKKi mediates B-DNA-mediated innate immune responses. Experiment Overall Design: Total RNA was extracted from embryonic fibroblats transfected for 4 h with or without poly(dA-dT)-poly(dT-dA), after which cRNA was synthesized. Preparation of cRNA, hybridization and scanning of the microarray were done according to the manufacturer's instructions (Affymetrix). A microarray (MG U74A version 2; Affymetrix) was used with Microarray Suite software (version 5.0; Affymetrix) and GeneSpring software (Silicon Genetics).
2007-12-07 | E-GEOD-4171 | biostudies-arrayexpress
Project description:b-cell proliferation induction is one of the most tangible therapeutic strategies to restore b-cell mass. However, this approach has proven challenging due to a remarkable resistance of adult human b-cells to proliferation. Here we aim to unravel the role of a non-canonical IkB kinase TBK1 (TANK-binding kinase 1), which is predominantly expressed in b-cells in mammalian islets, in regulating cell cycle progression. Genetic silencing of TBK1 in INS-1 832/13 rat b-cell line promoted proliferation of b-cells. Proteomic and transcriptome analyses further revealed changes of proteins and genes critical for cell growth and proliferation, including upregulation of ribosomal proteins and cell cycle regulators, upon depletion of TBK1. TBK1 overexpression decreased sensitivity of b-cells to the elevation of cAMP levels and reduced proliferation of b-cells in a manner dependent on the activity of phosphodiesterase 3 (PDE3). Importantly, pharmacological inhibition of TBK1 using (E)3-(3-phenylbenzo[c]isoxazol-5-yl) acrylic acid (PIAA) augmented proliferation and function of rat and human embryonic stem cell (hESC)-derived insulin-producing b-cells under basal conditions. Diabetogenic insults further induced TBK1 expression and accordingly, PIAA protected b-cells against cytokine- and streptozotocin-induced diabetogenic challenges and promoted b-cell replication. Furthermore, PIAA increased proliferation of β-cells in normal and type 2 diabetic human islets with elevation in insulin secretion. Altogether, these data unveil novel and essential function of TBK1 as a key cell-autonomous negative regulator of b-cell replication and presenting PIAA as a valid therapeutic strategy for augmenting proliferation and function of b-cells.
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Project description:T cells produce interferon gamma (IFNγ), but it is unclear whether they can use IFNγ to directly kill target cells. Here, we report that tumor targets lacking TBK1 and IKKε are killed by IFNγ, which induces expression of TNFR1 and the Z-nucleic acid sensor, ZBP1 to trigger RIPK1-dependent apoptosis. Concurrent with apoptosis, IFNγ unexpectedly also induces hyperactivation of NFκB in TBK1 and IKKε double-deficient cells. The two kinases normally function to inhibit IKKa/b activity and in their absence, IFNγ induces elevated expression of inflammatory genes. Thus, IFNγ can induce an inflammatory form of apoptosis that is normally suppressed by TBK1 and IKKε. These kinases regulate three responses: (1) induction of type I IFN; (2) inhibition of RIPK1-dependent death; and (3) inhibition of NFκB-dependent inflammation. We propose that these kinases evolved these intertwined functions so that cells infected by pathogens encoding TBK1/IKKε antagonists to block type I IFN expression will be killed by IFNγ-secreting T cells to generate an alternate NFκB-dependent inflammatory response.
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Project description:Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here we investigate how partial loss-of-function of TBK1, a major genetic cause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is an endogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice is dependent on RIPK1 kinase activity. In aging human brains, another endogenous RIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show that in Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the key hallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss and behavior deficits, which are blocked upon inhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to promote the onset of ALS/FTD.
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Project description:The purpose of the dataset is to analyze expression of genes induced by KRAS and regulated by TBK1; The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. Experiment Overall Design: Knock out of TBK1 in the contect of KRAS activation (mutant) and control (WT)
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Project description:Recent studies have demonstrated critical roles for TBK1 in regulation of activity of numerous immune cell types, including T cells, B cells, dendritic cells, and macrophages. To examine the effect of TBK1 inhibition on the tumor immune microenvironment, we performed scRNA-seq on CD45+ cells from B16-OVA tumors from mice treated with anti-PD-1, TBK1i, or anti-PD-1 plus TBK1i, compared to isotype control (IgG).
2022-11-10 | GSE217160 | GEO
Project description:We report here two unrelated HSE patients carrying different heterozygous mutations (D50A and G159A) in TBK1, the gene encoding TANK-binding kinase 1, a kinase at the crossroads of multiple IFN-inducing signaling pathways. Both mutant TBK1 alleles are loss-of-function, but through different mechanisms: protein instability (D50A) or a loss of kinase activity (G159A). Both are also associated with an autosomal dominant (AD) trait, but by different mechanisms: haplotype-insufficiency (D50A) or negative dominance (G159A). A defect in poly(I:C)-induced TLR3 responses can be detected in fibroblasts heterozygous for G159A, but not for D50A TBK1. Skin fibroblast cell lines were derived from healthy controls (n=3), patients with deficiencies for TBK1 (n=2), TLR3 (n=2), STAT1 (n=1) and cultured for 2 or 8 hours in the presence of IFNa (105 IU/ml), IL1b (20ng/ml), or poly I:C (25ug/ml) or left unstimulated for the same length of time.
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Project description:In-vivo inhibition of Fgfr2b signalling in embryonic mouse lungs
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