Ancestral function of Inhibitors-of-kappaB regulates Caenorhabditis elegans development (RNA-Seq)
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ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE146654 | GEO | 2020/09/01
REPOSITORIES: GEO
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Project description:NF-κB-mediated signaling is maintained silent by the action of IκB proteins, whose canonical role is to sequester NF-κB in the cytoplasm. An alternative chromatin role for IκB members have been shown to affect stemness and cell differentiation but the involvement of NF-κB in this function has not been excluded. NFKI-1 and IKB-1 are IκB homologs in Caenorhabditis elegans, which lacks NF-κB nuclear effectors. nfki-1 and ikb-1 mutants present developmental defects that phenocopy mutations in Polycomb genes and demethylases as utx-1. suggesting a role for C. elegans IKB proteins in chromatin regulation, which is supported by various lines of evidence:(i) we detected NFKI-1 in the nucleus; (ii) NFKI-1 and IKB-1 bind to histones and Polycomb proteins, (iii) NFKI-1 and IKB-1 bind to chromatin in vivo, and (iv) mutations in nfki-1 and ikb-1 alter chromatin marks . Thus, ancestral IκB inhibitors may exert nuclear functions regulating of gene expression and development.
2020-09-01 | GSE146652 | GEO
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Project description:Gastric mucosa responds to the pathogen Helicobacter pylori (H. pylori) by producing and release of pro-inflammatory cytokines that activate the innate immune system mainly through activation of the transcription factor NF-κB. Although NF-κB signaling is well studied for many possible inducers, induction by H. pylori remains poorly understood. Here, we performed a high-throughput genome-wide RNAi screen for genes influencing H. pylori-induced NF-κB activation. In comparison to TNFα or IL‐1β NF‐κB signaling, we identified 21 proteins unique necessary for H. pylori NF-κB pathway and 24 factors that inhibited the activation. Furthermore, we present here the R/Bioconductor package Nested Effect Model for systematic use in high-throughput screens to classify newly identified factors. We identified alpha kinase 1 (ALPK1) as particular important for the H. pylori NF‐κB pathway without affecting TNFα or IL‐1β signaling. ALPK1 silencing inhibits activity of TAK1 and the IκB kinases (IKKs), degradation of the NF‐κB inhibitor IκBα, nuclear translocation of the NF‐κB subunit p65, and transcription of the NF‐κB target genes, e.g. IL‐8. Thus, we identify ALPK1 as a novel inflammatory regulator functioning particularly in the NF‐κB signaling network activated by H. pylori.
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Project description:The model was constructed to describe TLR4 induced NF-κB activation in native bone marrow-derived macrophages. It included processes of ligand (lipopolysaccharide) recognition, formation of dimer receptor complex and further signal transduction through TRAF6/TAK1 complex that leads to the activation of IKKα/β kinase, which in turn enables the NF-κB transcription factor phosphorylation and translocation in the cell nucleus, and induction of IkB and WIP1 (as an example of induced protein that promotes NF-κB dephosphorylation 2) gene transcription. Models were based on the current knowledge of TLR signaling framework, protein interactions within the TLR4 pathway, and up-to-date mathematical models describing Toll receptor activation.
The major important additions were made to TLR4 signaling description:
1) Receptor dimerization process
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2011-01-08 | E-GEOD-26490 | biostudies-arrayexpress
Project description:The intracellular bacterial pathogen Legionella pneumophila causes an inflammatory pneumonia called Legionnaires’ Disease. For virulence, L. pneumophila requires a Dot/Icm type IV secretion system that translocates bacterial effectors to the host cytosol. L. pneumophila lacking the Dot/Icm system is recognized by Toll-like receptors (TLRs), leading to a canonical NF-κB-dependent transcriptional response. In addition, L. pneumophila expressing a functional Dot/Icm system potently induces unique transcriptional targets, including proinflammatory genes such as Il23a and Csf2. Here we demonstrate that this Dot/Icm-dependent response, which we term the effector-triggered response (ETR), requires five translocated bacterial effectors that inhibit host protein synthesis. Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor. Thus, macrophages infected with wildtype L. pneumophila exhibited prolonged activation of NF-κB, which was associated with transcription of ETR target genes such as Il23a and Csf2. L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR. L. pneumophila mutants expressing enzymatically inactive effectors were also unable to fully induce the ETR, whereas multiple compounds or bacterial toxins that inhibit host protein synthesis via distinct mechanisms recapitulated the ETR when administered with TLR ligands. Previous studies have demonstrated that the host response to bacterial infection is induced primarily by specific microbial molecules that activate TLRs or cytosolic pattern recognition receptors. Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis. Four-condition experiment: macrophages left uninfected (negative control), or infected with wildtype Legionella pneumophila, the flagellin-deficient mutant ΔflaA, or the secretion-deficient mutant ΔdotA (three experimental conditions). Biological replicates: two, independently infected, harvested, and hybridized to arrays. One to two technical replicates per array, as indicated in file titles.
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