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Impaired glycosylation drives golgi stress-mediated gastric tumorigenesis that can be targeted by lectin-drug conjugates II

ABSTRACT: Impaired glycosylation drives golgi stress-mediated gastric tumorigenesis that can be targeted by lectin-drug conjugates II

PROVIDER: PRJNA996164 | ENA |

REPOSITORIES: ENA

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Impaired glycosylation drives golgi stress-mediated gastric tumorigenesis that can be targeted by lectin-drug conjugates

Project description:Downregulation or gene mutation of MUC6, a major component of gastric mucin, is often identified in human gastric cancers. However, the mechanistic role of MUC6 alteration in gastric carcinogenesis remains unclear. Here, using Muc6-deficient mice, we revealed that dysregulated glycosylation in Muc6-deficient gastric epithelium causes aberrant golgi stress responses, resulting in spontaneous gastric cancer development. Muc6-deficient tumor growth is dependent on MAPK activation, which is mediated by golgi stress-induced golph3 upregulation. Glycomic analysis and lectin-binding assays revealed abnormal expression of mannose-rich N-type glycans in Muc6-deficient gastric tumors. Banana lectin-drug conjugates, which bind to mannose-rich glycans, dramatically suppress mannose-rich murine and human gastric cancer growth. Thus, we propose golgi stress responses and aberrant sugar chains as promising therapeutic targets in gastric cancers accompanied with mucin expression disorder.

2024-08-31 | GSE237686 | GEO

Impaired glycosylation drives golgi stress-mediated gastric tumorigenesis that can be targeted by lectin-drug conjugates

2024-08-31 | GSE237822 | GEO

Impaired glycosylation drives golgi stress-mediated gastric tumorigenesis that can be targeted by lectin-drug conjugates II

2024-08-31 | GSE237689 | GEO

Impaired glycosylation drives golgi stress-mediated gastric tumorigenesis that can be targeted by lectin-drug conjugates

Project description:Impaired glycosylation drives golgi stress-mediated gastric tumorigenesis that can be targeted by lectin-drug conjugates

| PRJNA996883 | ENA

Impaired glycosylation drives golgi stress-mediated gastric tumorigenesis that can be targeted by lectin-drug conjugates

Project description:Impaired glycosylation drives golgi stress-mediated gastric tumorigenesis that can be targeted by lectin-drug conjugates

| PRJNA996161 | ENA

Trans-Golgi protein TVP23B regulates host-microbe interactions via Paneth cell homeostasis and Goblet cell glycosylation

Project description:A key feature in intestinal immunity is the dynamic intestinal barrier, which separates the host from resident and pathogenic microbiota through a mucus gel impregnated with antimicrobial peptides. The mechanisms underlying the maintenance and function of this intestinal barrier are not completely understood. Using a mouse forward genetic screen for defects of intestinal homeostasis, we have found a mutation in Tvp23b, which conferred susceptibility to chemically induced and infectious colitis. Golgi apparatus membrane protein TVP23 homolog B (TVP23B) is a transmembrane protein conserved from yeast to humans. In the intestine, the protein is localized to the epithelium and its deficiency in the hematopoietic extrinsic compartment was essential to the colitis phenotype. We found that TVP23B controls the homeostasis of Paneth cells and function of goblet cells in vivo, leading to a decrease in antimicrobial peptides as well as a more penetrable mucus layer. As a result, Tvp23b-/- mice displayed decreased barrier function and a loss of host-microbe separation. TVP23B-deficient colonocytes have a loss of core-3 O-glycosylation of colonic proteins, which is the major O-glycosylation present on gel forming mucins. TVP23B binds with another Golgi protein, YIPF6, which is similarly critical for intestinal homeostasis. The Golgi proteomes of YIPF6 and TVP23B-deficent colonocytes have a common deficiency of several critical glycosylation enzymes, including those necessary for core-3 glycosylation of mucins. TVP23B is necessary for the formation of the sterile mucin layer of the intestine and its absence disturbs the balance of host and microbe in vivo.

2023-08-03 | GSE224516 | GEO

Transcriptome analysis of the Golgi stress response

Project description:We explore the transcriptional response of mammalian cells undergoing various insults to Golgi homeostasis. HEK293 cells (Flp-In T-REx 293 cells) stably containing a doxycycline-inducible Golgi-localized HaloTag2 construct (GA-HT2) were treated with the ionophore nigericin, the glycosylation inhibitor xyloside, or were induced by doxycycline and treated with the hydrophobic tag HyT36 to induce destabilization of GA-HT2. We found that while nigericin and xyloside induce global transcriptional changes, destabilization of GA-HT2 induces a Golgi-specific response.

2018-06-21 | GSE99490 | GEO

Trans-Golgi protein TVP23B regulates host-microbe interactions via Paneth cell homeostasis and Goblet cell glycosylation

Project description:Trans-Golgi protein TVP23B regulates host-microbe interactions via Paneth cell homeostasis and Goblet cell glycosylation

| PRJNA931370 | ENA

Genome wide transcriptomics analyses of livers reveal induction of N-glycosylation upon loss of nuclear receptors FXR and SHP

Project description:We performed high-throughput RNA-sequencing on livers from hepatocyte specific Fxr-/- Shp-/- double knockout mice, and identified upregulation of N-glycan protein modification machinery. This correlated positively with Golgi structural defects and alterations in the hepatic secretome. This study identifies a new role for hepatic FXR-SHP axis in Golgi dynamics and N-glycosylation, apart from its traditional function in nutrient metabolism.

2021-03-09 | GSE164447 | GEO

Pancreatic β cell SERCA2 deficiency leads to impaired proinsulin processing and reduced ER to Golgi protein trafficking

Project description:Impaired proinsulin processing is observed in both type 1 and type 2 diabetes. We have previously shown that reductions in endoplasmic reticulum (ER) calcium (Ca2+) in the pancreatic β cell arising from impaired activity of the Sarcoendoplasmic Reticulum Ca2+ ATPase (SERCA) pump are associated with increased proinsulin secretion. However, the mechanisms responsible for reduced proinsulin processing in the context of SERCA2 deficiency remain incompletely understood. To test this, we developed mice with β cell specific SERCA2 deletion (βS2KO mice) and S2KO INS1 cells. βS2KO mice exhibited age-dependent glucose intolerance and reduced glucose-stimulated insulin secretion without evidence of impaired insulin sensitivity. ER Ca2+ levels in islets from βS2KO mice were significantly reduced, while serum proinsulin/insulin (PI/I) ratios and whole pancreas PI/I content were elevated. Immunoblot analysis of βS2KO islets and S2KO INS-1 cells revealed reduced active forms of the proinsulin processing enzymes, PC1/3, PC2 and CPE. Restoration of SERCA2b via adenoviral transduction in S2KO INS1 cells was sufficient to restore PC1/3 and PC2 maturation and enzyme activity. Brefeldin A treatment in INS1 cells recapitulated the impairments in PC1/3 and PC2 maturation observed in S2KO cells, suggesting a disturbance in protein trafficking between the ER and Golgi. Consistent with this, trafficking assays were performed using a vesicular stomatitis virus G (VSVG) protein construct and revealed a significantly slower rate of VSVG movement from the ER to the Golgi in S2KO INS1 cells. Moreover, pancreas sections from βS2KO mice showed increased co-localization of proinsulin and ProPC2 in the early compartments of the secretory pathway. Taken together, these data suggest that loss of SERCA2 activity and ER Ca2+ loss in the pancreatic β cell leads to impaired proinsulin processing via reduced maturation and trafficking of proinsulin processing enzymes.

2023-10-11 | GSE207498 | GEO

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