Interleukin-22 (IL-22) regulates B3GNT7 expression to induce intestinal fucosylation of O-linked glycans
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ABSTRACT:
PROVIDER: PRJNA647688 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12285704.fastq.gz | Fastqsanger.gz | |||
| SRR12285705.fastq.gz | Fastqsanger.gz | |||
| SRR12285706.fastq.gz | Fastqsanger.gz | |||
| SRR12285707.fastq.gz | Fastqsanger.gz | |||
| SRR12285708.fastq.gz | Fastqsanger.gz |
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Project description:Interleukin (IL) - 22 is a cytokine that plays a critical role in the maintenance of intestinal epithelial homeostasis. Its downstream functions are mediated through ligation of its heterodimeric receptor comprised of IL-22 receptor subunit alpha 1 (IL-22Ra1) and IL-10R2, and subsequent activation of signal transducer and activator of transcription 3 (STAT3). IL-22 signaling can induce genes necessary for intestinal epithelial cell proliferation, tissue regeneration, tight junction fortification, and production of antimicrobials. Emerging studies have also implicated IL-22 signaling in the regulation of intestinal epithelial fucosylation in mice. However, whether IL-22 regulates intestinal fucosylation in human intestinal epithelial cells and the molecular mechanisms that govern this process are unknown. Here, we show that IL-22 signaling regulates expression of the B3GNT7 transcript, which encodes a β1-3-N-acetylglucosaminyltransferase that can participate in the synthesis of poly-N-acetyllactosamine (LacNAc) chains. Additionally, we show that IL-22 signaling regulates levels of the a1-3-fucosylated Lewis X (Lex) blood group antigen and this glycan epitope is primarily displayed on heavily O-glycosylated intestinal epithelial glycoproteins. The IL-22-mediated increase in Lex antigen levels requires B3GNT7, as disruption of B3GNT7 expression moderated the IL-22-dependent increase in Lex antigen levels. Moreover, we show that increased expression of B3GNT7 alone is sufficient to promote increased display of Lex-decorated carbohydrate glycan structures primarily on O-glycosylated intestinal epithelial glycoproteins. Together, the data presented here identify B3GNT7 as a critical intermediary in IL-22-dependent induction of intestinal fucosylation of O-linked glycans and uncover a novel role for B3GNT7 in intestinal glycosylation.
2021-11-27 | GSE154889 | GEO
Project description:Interleukin (IL)-22 is a cytokine that plays a critical role in intestinal epithelial homeostasis. Its downstream functions are mediated through interaction with the heterodimeric IL-22 receptor and subsequent activation of signal transducer and activator of transcription 3 (STAT3). IL-22 signaling can induce transcription of genes necessary for intestinal epithelial cell proliferation, tissue regeneration, tight junction fortification, and antimicrobial production. Recent studies have also implicated IL-22 signaling in the regulation of intestinal epithelial fucosylation in mice. However, whether IL-22 regulates intestinal fucosylation in human intestinal epithelial cells and the molecular mechanisms that govern this process are unknown. Here, in experiments performed in human cell lines and human-derived enteroids, we show that IL-22 signaling regulates expression of the B3GNT7 transcript, which encodes a β1-3-N-acetylglucosaminyltransferase that can participate in the synthesis of poly-N-acetyllactosamine (polyLacNAc) chains. Additionally, we find that IL-22 signaling regulates levels of the α1-3-fucosylated Lewis X (Lex) blood group antigen, and that this glycan epitope is primarily displayed on O-glycosylated intestinal epithelial glycoproteins. Moreover, we show that increased expression of B3GNT7 alone is sufficient to promote increased display of Lex-decorated carbohydrate glycan structures primarily on O-glycosylated intestinal epithelial glycoproteins. Together, these data identify B3GNT7 as an intermediary in IL-22-dependent induction of fucosylation of glycoproteins and uncover a novel role for B3GNT7 in intestinal glycosylation.
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2024-10-09 | GSE266340 | GEO
Project description:Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post59 translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In both cancer cell cultures and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycomes revealed that fucosylation of the antioxidant PON1 is a critical component of the therapy66 induced secretome. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Non-specific and PON1-specific secretome deglycosylation both limited the expansion of resistant clones in a tumor regression model. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.
2023-04-05 | GSE160205 | GEO
Project description:Systemic infection induces conserved physiological responses that include both resistance and ‘tolerance of infection’ mechanisms. Among these responses, temporary anorexia associated with an infection is often beneficial. It poses, however, a problem for the trillions of microbes residing in the gastrointestinal tract, as they also experience reduced substrate availability. We hypothesized that under anorectic conditions caused by infection, the host might activate protective mechanisms to support the gut microbiota during the acute phase of the disease. Here, we report that systemic exposure to Toll-like receptor (TLR) ligands causes rapid α1,2-fucosylation of the small intestine epithelial cells (IEC). The process requires sensing of TLR agonists and production of IL-23 by dendritic cells, activation of innate lymphoid cells and expression of α1,2-Fucosyltransferase-2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is utilized by microbiota, as shown using reporter bacteria and by transcriptional profiling of the gut microbiome. Fucosylation also reduces the expression of bacterial virulence genes within the commensal gut microbiome and improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host’s resources to maintain host-microbial interactions during pathogen-induced stress. RNA-Seq analysis of the murine gut microbiome following LPS exposure. Fut2-/- (B6.129X1-Fut2tm1Sdo/J) mice were backcrossed greater than 7 generations to BALB/c. Fut2-/- (KO) and Fut2+/- (Het) animals were analyzed.
2014-10-24 | E-GEOD-60874 | biostudies-arrayexpress
Project description:T cells are key players in immunosurveillance and anti-tumor immunity. However, subsets of T helper cells producing high levels of interleukin-22 (IL-22) accumulate in primary breast and lung tumors and are linked to a more dismal outcome. Here, we demonstrate that such TH22 cells promote metastasis by abrogating NK cell-mediated immune surveillance. Using mouse models of metastatic lung and breast cancer, we find that secreted IL-22 acts directly on disseminated cancer cells expressing the IL-22 receptor (IL-22R). In turn, IL-22 induces cancer cell overexpression of CD155, which binds to activating receptor CD226 on the surface of NK cells and triggers its downregulation. This functionally impairs NK cells to promote lung metastases. Importantly, neutralization of IL-22 in vivo blocked the metastatic potential of cancer cells, suggestive of therapeutic exploitability. We confirmed the paramount role of IL-22 signaling that was associated with CD155 expression in human datasets and marked poor patient outcomes. This study reveals an immunosuppressive feedback loop activated by T cell-derived IL-22 in cancer progression, creating the rationale for the development of future targeted therapeutics.
2022-06-30 | GSE202314 | GEO
Project description:Systemic infection induces conserved physiological responses that include both resistance and ‘tolerance of infection’ mechanisms. Among these responses, temporary anorexia associated with an infection is often beneficial. It poses, however, a problem for the trillions of microbes residing in the gastrointestinal tract, as they also experience reduced substrate availability. We hypothesized that under anorectic conditions caused by infection, the host might activate protective mechanisms to support the gut microbiota during the acute phase of the disease. Here, we report that systemic exposure to Toll-like receptor (TLR) ligands causes rapid α1,2-fucosylation of the small intestine epithelial cells (IEC). The process requires sensing of TLR agonists and production of IL-23 by dendritic cells, activation of innate lymphoid cells and expression of α1,2-Fucosyltransferase-2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is utilized by microbiota, as shown using reporter bacteria and by transcriptional profiling of the gut microbiome. Fucosylation also reduces the expression of bacterial virulence genes within the commensal gut microbiome and improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host’s resources to maintain host-microbial interactions during pathogen-induced stress.
2014-10-24 | GSE60874 | GEO
Project description:Human serum IgM antibodies are composed of heavily glycosylated polymers with five glycosylation sites on the μ (heavy) chain and one glycosylation site on the J chain. In contrast to IgG glycans, which are vital for a number of biological functions, virtually nothing is known about structure-function relationships of IgM glycans. Natural IgM is the earliest immunoglobulin produced and recognizes multiple antigens with low affinity, whilst immune IgM is induced by antigen exposure and is characterized by a higher antigen specificity. Natural anti-lymphocyte IgM is present in the serum of healthy individuals and increases in inflammatory conditions. It is able to inhibit T cell activation, but the underlying molecular mechanism is not understood. Here we show, for the first time, that sialylated N-linked glycans induce the internalization of IgM by T cells, which in turn causes severe inhibition of T cell responses. The absence of sialic acid residues abolishes these inhibitory activities, showing a key role of sialylated N-glycans in inducing the IgM-mediated immune suppression.
2014-11-11 | E-MTAB-3030 | biostudies-arrayexpress
Project description:Activation of murine CD4+ and CD8+ T lymphocytes leads to dramatic remodeling of N-linked glycans. Naïve and activated CD4 T cells, CD8 T cells and B cells were compared for their N-linked glycan structures by MALDI-TOF MS profiling and for expression of glycan transferase genes to assess the biosynthetic basis for any change observed. The major change observed in activated CD4 and CD8 T cells was dramatic reduction of sialylated bi-antennary N-glycans carrying the terminal NeuGc?2-6Gal sequence, and corresponding increase in glycans carrying the Gal?1-3Gal sequence. This change was accounted for by a decrease in the expression of the sialyltransferase ST6Gal, and increase in the expression of the galactosyltransferase ?1-3GalT. Conversely, in B cells no change in terminal sialylation of N-linked glycans was evident, and the expression of the same two glycosyltransferases were increased and decreased, respectively. Keywords = N-linked glycosylation, T cell, B cell, activation, glycosyltransferase, carbohydrate, glycomics, glycan, galactosyltransferase, sialyltransferase Keywords: other
2005-05-03 | GSE2554 | GEO
Project description:T cells produce interleukin-22 to promote CD155-driven lung metastasis
| PRJNA835449 | ENA