TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE153924 | GEO | 2020/07/08
REPOSITORIES: GEO
Similar Datasets
Project description:TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin
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Project description:Macrophage activation by bacterial lipopolysaccharides (LPS) is induced through Toll-like receptor 4 (TLR4). The synthesis and activity of TLR4 downstream signalling molecules modulates the expression of pro- and anti-inflammatory cytokines. To address the impact of post-transcriptional regulation on that process, we performed RIP-Chip analysis. Differential association of mRNAs with heterogeneous ribonucleoprotein K (hnRNP K), an mRNA-specific translational regulator in differentiating haematopoietic cells, was studied in non-induced and LPS-activated macrophages. Analysis of interactions affected by LPS revealed an enrichment of mRNAs encoding TLR4 downstream kinases and their modulators. We focused on transforming growth factor β activated kinase-1 (TAK1), a central player in TLR4 signalling. HnRNP K interacts specifically with a sequence in the TAK1 mRNA 3' UTR in vitro. Silencing of hnRNP K does not affect TAK1 mRNA synthesis and stability, but enhances TAK1 mRNA translation, resulting in elevated TNF-alpha, IL-1beta and IL-10 mRNA expression. Our data suggest that the hnRNP K-3' UTR complex inhibits TAK1 mRNA translation in non-induced macrophages. LPS-dependent TLR4 activation abrogates translational repression and newly synthesised TAK1 initiates the inflammatory response of macrophages. In this dataset, we include expression data of RAW 264.7 cells comparing untreated cells and 6h Lipopolysaccharide treatment, and analyse RNAs co-precipitating with hnRNP K dependent on LPS treatment. 12 total samples were analyzed, 6 samples of 2 biological replicates.
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Project description:For a sperm to successfully fertilize an egg, it must first undergo capacitation in the female reproductive tract, and later undergo acrosomal reaction (AR) upon encountering an egg. How premature AR is avoided despite rapid surges in signaling cascades during capacitation remains unknown. Using a combination of KO mice and cell-penetrating peptides, here we show that GIV (CCDC88A), a guanine nucleotide-exchange factor (GEM) for trimeric GTPases, is highly expressed in spermatocytes and is required for male fertility. GIV is rapidly phosphoregulated on key tyrosine and serine residues in human and murine sperms. These phosphomodifications enable GIV-GEM to orchestrate two distinct compartmentalized signaling programs in the sperm tail and head; in the tail, GIV enhances PI3K→Akt signals, sperm motility and survival, whereas in the head it inhibits cAMP surge and premature AR. Furthermore, GIV transcripts are downregulated in the testes and semen of infertile men. These findings exemplify the spatiotemporally segregated signaling programs that support sperm capacitation and the etiology of infertility in men.
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Project description:PDZ domains are one of the most abundant protein domains in eukaryotes and frequently found on junction-localized scaffold proteins. Various signaling molecules bind to PDZ proteins via PDZ-binding motifs (PBM) and finetune cellular signaling. Here we describe the presence of a PBM on GIV/Girdin (CCDC88A) that is conserved throughout evolution, from invertebrates to vertebrates, and is generated as a long isoform-variant in humans, which we named GIV-L. Unlike GIV, which lacks PBM and is cytosolic, GIV-L localizes to the cell junctions, and has a unique PDZ-interactome, which impacts GIV-L’s ability to bind and activate trimeric G-protein, Gi through its guanine-nucleotide exchange modulator (GEM) module; the GEM module is found exclusively in vertebrates. Thus, the two functional modules in GIV evolved sequentially: the ability to bind PDZ proteins via the PBM evolved earlier in invertebrates, whereas G-protein binding and activation may have evolved later only among vertebrates. Phenotypic studies in Caco-2 cells revealed that GIV and GIV-L may have antagonistic effects on cell growth, proliferation (cell cycle), and survival. Immunohistochemical analyses in human colon tissues showed that GIV expression increases with a concomitant decrease in GIV-L during cancer initiation. Taken together, these findings reveal how GIV/CCDC88A in humans displays evolutionary flexibility in modularity, which allows the resultant isoforms to play opposing roles either as a tumor suppressor (GIV-L) or as an oncogene (GIV).
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Project description:Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions using tumor-MSC co-cultures and using an integrated transcriptome-proteome-network-analyses workflow identified a comprehensive catalog of contact-induced changes. Induced genes/proteins—some borrowed and others tumor-intrinsic response—were not recapitulated merely by conditioned media. Protein-protein interaction networks reveal the rich connectome between the ‘borrowed’ and ‘intrinsic’ components. Bioinformatic analyses helped prioritize one of the ‘borrowed’ components, CCDC88A/GIV, a bona-fide multi-modular metastasis-related protein. MSCs upregulated GIV in ER+ breast cancer cells through connexin (Cx)43-facilitated intercellular long-distance transport. Stable expression of GIV recapitulated ~20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patters observed during contact cocultures, conferred resistance to clinical anti-estrogen drugs, and enhanced tumor dissemination. These data provide a multiomic insight into the role of MSC→tumor cell intercellular transport and validate as proof-of-concept how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.
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Project description:Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions using tumor-MSC co-cultures and using an integrated transcriptome-proteome-network-analyses workflow identified a comprehensive catalog of contact-induced changes. Induced genes/proteins—some borrowed and others tumor-intrinsic response—were not recapitulated merely by conditioned media. Protein-protein interaction networks reveal the rich connectome between the ‘borrowed’ and ‘intrinsic’ components. Bioinformatic analyses helped prioritize one of the ‘borrowed’ components, CCDC88A/GIV, a bona-fide multi-modular metastasis-related protein. MSCs upregulated GIV in ER+ breast cancer cells through connexin (Cx)43-facilitated intercellular long-distance transport. Stable expression of GIV recapitulated ~20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patters observed during contact cocultures, conferred resistance to clinical anti-estrogen drugs, and enhanced tumor dissemination. These data provide a multiomic insight into the role of MSC→tumor cell intercellular transport and validate as proof-of-concept how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.
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Project description:Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions using tumor-MSC co-cultures and using an integrated transcriptome-proteome-network-analyses workflow identified a comprehensive catalog of contact-induced changes. Induced genes/proteins—some borrowed and others tumor-intrinsic response—were not recapitulated merely by conditioned media. Protein-protein interaction networks reveal the rich connectome between the ‘borrowed’ and ‘intrinsic’ components. Bioinformatic analyses helped prioritize one of the ‘borrowed’ components, CCDC88A/GIV, a bona-fide multi-modular metastasis-related protein. MSCs upregulated GIV in ER+ breast cancer cells through connexin (Cx)43-facilitated intercellular long-distance transport. Stable expression of GIV recapitulated ~20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patters observed during contact cocultures, conferred resistance to clinical anti-estrogen drugs, and enhanced tumor dissemination. These data provide a multiomic insight into the role of MSC→tumor cell intercellular transport and validate as proof-of-concept how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.
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Project description:Macrophage activation by bacterial lipopolysaccharides (LPS) is induced through Toll-like receptor 4 (TLR4). The synthesis and activity of TLR4 downstream signalling molecules modulates the expression of pro- and anti-inflammatory cytokines. To address the impact of post-transcriptional regulation on that process, we performed RIP-Chip analysis. Differential association of mRNAs with heterogeneous ribonucleoprotein K (hnRNP K), an mRNA-specific translational regulator in differentiating haematopoietic cells, was studied in non-induced and LPS-activated macrophages. Analysis of interactions affected by LPS revealed an enrichment of mRNAs encoding TLR4 downstream kinases and their modulators. We focused on transforming growth factor β activated kinase-1 (TAK1), a central player in TLR4 signalling. HnRNP K interacts specifically with a sequence in the TAK1 mRNA 3' UTR in vitro. Silencing of hnRNP K does not affect TAK1 mRNA synthesis and stability, but enhances TAK1 mRNA translation, resulting in elevated TNF-alpha, IL-1beta and IL-10 mRNA expression. Our data suggest that the hnRNP K-3' UTR complex inhibits TAK1 mRNA translation in non-induced macrophages. LPS-dependent TLR4 activation abrogates translational repression and newly synthesised TAK1 initiates the inflammatory response of macrophages. In this dataset, we include expression data of RAW 264.7 cells comparing untreated cells and 6h Lipopolysaccharide treatment, and analyse RNAs co-precipitating with hnRNP K dependent on LPS treatment.
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Project description:Among the diseases caused by Toll-like receptor 4 (TLR4) abnormal activation by bacterial endotoxin, sepsis is the most dangerous one. The reprogramming of macrophages plays a crucial role in orchestrating the pathogenesis of sepsis. However, the precise mechanism underlying TLR4 activation in macrophages remained incompletely understood. Our studies revealed that upon lipopolysaccharide (LPS) stimulation, CREB-binding protein (CBP) was recruited to the TLR4 signalosome complex and resulted in pronounced acetylation in the TIR domains of TLR4, Myeloid differentiation factor 88 (MyD88) and MyD88 adapter-like (MAL), which significantly enhanced the activation of the NF-κB signaling pathway and polarization of M1 macrophages. In sepsis patients, significantly elevated TLR4-TIR acetylation was detected in CD16+ monocytes combined with elevated expression of M1 macrophage markers and production of pro-inflammatory cytokines. In contrast, histone deacetylase 1 (HDAC1) served as a key deacetylase in the deacetylation of the TIR domain complex. The inhibition of HDAC1 accelerated sepsis-associated syndromes, while the inhibition of CBP alleviated this process. Overall, our findings highlighted the crucial role of TIR domain complex acetylation in the regulation of inflammatory immune response and suggested that the reversible acetylation of the complex emerged as a promising therapeutic target for M1 macrophages during the progression of sepsis.
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2010-10-01 | E-GEOD-21895 | biostudies-arrayexpress