Impact of G167R mutation in CHUK gene, coding for IKKα protein, on gene expression in PBMCs
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1080009 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28083124_1.fastq.gz | Fastqsanger.gz | |||
| SRR28083124_2.fastq.gz | Fastqsanger.gz | |||
| SRR28083125_1.fastq.gz | Fastqsanger.gz | |||
| SRR28083125_2.fastq.gz | Fastqsanger.gz |
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Project description:IKKα is a critical regulator of the non-canonical NF-KB signalling pathway. In patients with combined immunodeficiency, we identified a homozygous missense mutation in CHUK gene, coding for IKKα protein, leading to G167R amino acid change in the kinase domain of the protein. This mutation impairs the kinase activity of IKKα, which results in a range of aberratins in innate and adaptive immunity.
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Project description:Depending on the tumor type IκB kinase α (IKKα) can act as tumor promoter or tumor suppressor in various malignancies. Here we demonstrate a key function of IKKα in the suppression of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of IFNγ expressing M1-like myeloid cells. In IKKα mutant mice M1-like polarization is not controlled in a cell autonomous manner but depends rather on the interplay of both IKKα mutant tumor epithelia and immune cells.
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Project description:We generated Ikkα-KA/KA knock-in mice (KA/KA), in which an ATP binding site of Ikkα Lys 44 was replaced by alanine. The knock-in mice develop severe skin lesions and begin to die after 6 to 10 months. We also found lung SCCs in some of the mice. To study lung SCC development, we stabilize the skin condition by crossing KA/KA with Lori.Ikkα transgenic mice to generate KA/KA-Lori.Ikkα mice, which 100% spontaneously developed lethal lung SCC at 4 to 6 months of age. Clodronate-liposomes obtained from Dr. N. van Rooijen (Vrije Universiteit, Amsterdam, Netherlands) were intravenously injected into mice twice every week, started in 4 weeks old mice, and continued for 3 months. The dose of clodronate-liposomes was 100µl during the first month and elevated to 150 100µl after that. The depletion efficacy was confirmed by detecting pulmonary macrophages with Flow Cytometry. Depletion of macrophages in these KA/KA-Lori.Ikkα mice could significantly reduce inflammation and prevent lung SCC developmrnt. This aim of this microarray assay is to identify differentially expressed genes among Wild type, KA/KA-Lori.Ikkα, and macophage-depleted KA/KA-Lori.Ikkα mice, which may highlight the important genes or parthways involved in inflammation-associated lung SCC carcinogenesis. Three samples were analyzed: 1. WT (lung tissue from wild type mouse); 2. KA2 (mixture tissue of lung SCC and tumor neighbor from KA/KA-Lori-Ikkα mouse ); 3. KAT (lung tissue from KA/KA-Lori-Ikkα mouse with macrophage depletion treatment)
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Project description:Hepatitis C virus interacts extensively with host factors not only to establish productive infection but also to trigger unique pathological processes. Our recent genome-wide siRNA screen demonstrated that IKKα is a critical host factor for HCV. Here we describe a novel NF-κB-independent and kinase-mediated nuclear function of IKKα in HCV assembly. HCV infection, through its 3’-untranslated region, interacts with DDX3X to activate IKKα, which translocates to the nucleus and induces a CBP/p300-mediated transcriptional program involving SREBPs. This novel innate pathway induces lipogenic genes and enhances core-associated lipid droplet formation to facilitate viral assembly. Chemical inhibitors of IKKα suppress HCV infection and IKKα-induced lipogenesis, offering a proof-of-concept approach for novel HCV therapeutic development. Our results show that HCV commands a novel mechanism to its advantage by exploiting intrinsic innate response and hijacking lipid metabolism, which likely contributes to a high chronicity rate and the pathological hallmark of steatosis in HCV infection. Cells were treated with either non-targeting control siRNA or siRNA against IKKalpha. After 72 h, cells were either mock infected or infected with HCV JFH-1 strain with the M.O.I. of 0.5.
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Project description:IKKα kinase is essential for the B cell maturation and secondary lymphoid organ development. In the current study, we evaluated the role of IKKα in the marginal zone and follicular B lymphocyte development by genetically deleting IKKα from the B cell lineage using CD19-Cre mice. The loss of IKKα did not affect the normal development of early B cell progenitors. However, a significant decline was observed in the percentage of immature B lymphocytes, mature marginal zone and follicular B cells along with a severe disruption of splenic marginal and follicular B cell zones. A gene expression analysis performed on the RNA extracted from the newly formed B cells (B220+IgMhi) revealed that IKKα deficiency produces significant changes in the expression of genes involved in MZ and FO B lymphocyte survival, homing and migration. And several among those genes identified belong to G protein family. Specifically, we validated the upregulated expression of regulator of G protein signaling 13 (RGS13), which is a GTPase activating protein (GAP) that negatively regulates G protein signaling and impede B cell migration. Likewise, promigratory B lymphocyte receptor, the sphingosine-1-phosphate receptor 3 (SIPR3) that couple to Gαi showed significantly reduced expression. In addition, an in silico analysis of gene product interactions revealed NF-κB signaling pathways to be a major gene regulating networks perturbed with IKKα deletion. Taken together, this study reveals IKKαNF-κB and G protein signaling axis to be central for the MZ and FO B cells survival, maintenance, homing and migration.
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