Human defensin 5 activates purinergic receptor P2Y11, inducing filopodial extensions hijacked by Shigella for invasion
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Dan Xu
PROVIDER: PXD047689 | iProX | Tue Dec 12 00:00:00 GMT 2023
REPOSITORIES: iProX
Similar Datasets
Project description:Human enteric α-defensin 5 (HD5) acts as a “double-edged sword” in host immunity due to its prominent role in promoting pathogen infections, yet the mechanistic basis of its infection-enhancing operation remains unclarified. Here we show that HD5 induces abundant filopodial extensions in epithelial cells which capture Shigella, a major human enteroinvasive pathogen that exploits filopodia for invasion, at high efficiency, suggesting a novel human-specific mechanism of HD5-augmented bacterial invasion. Using multi-omics screening and both gut-on-chip and in vivo models, we identify the HD5 receptor as P2Y11, a purinergic receptor distributed apically on the luminal surface of human colonic epithelium, which to our knowledge is the first HD5 receptor for a specific cellular function. cAMP-PKA signaling was identified to be the main pathway mediating the cytoskeleton-regulating activity of HD5, whose critical residues involved were also determined. In illuminating this mechanism of Shigella invasion, our findings raise the possibility of new intervention strategies against HD5-augmented infections.
2024-12-16 | PXD057832 | Pride
Project description:Human enteric α-defensin 5 (HD5) acts as a “double-edged sword” in host immunity due to its prominent role in promoting pathogen infections, yet the mechanistic basis of its infection-enhancing operation remains unclarified. Here we show that HD5 induces abundant filopodial extensions in epithelial cells which capture Shigella, a major human enteroinvasive pathogen that exploits filopodia for invasion, at high efficiency, suggesting a novel human-specific mechanism of HD5-augmented bacterial invasion. Using multi-omics screening and both gut-on-chip and in vivo models, we identify the HD5 receptor as P2Y11, a purinergic receptor distributed apically on the luminal surface of human colonic epithelium, which to our knowledge is the first HD5 receptor for a specific cellular function. cAMP-PKA signaling was identified to be the main pathway mediating the cytoskeleton-regulating activity of HD5, whose critical residues involved were also determined. In illuminating this mechanism of Shigella invasion, our findings raise the possibility of new intervention strategies against HD5-augmented infections.
2024-11-14 | PXD057873 |
Project description:Acute myeloid leukemia (AML) is a type of heterogeneous and fatal hematopoietic malignancy. The ten-eleven translocation (TET) mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we found that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, were then verified in AML cells in vitro, and t(11q23) and t(8;21) AML mouse models in vivo. OPA1-induced activation of OPRM1 enhanced the transcription of TET2, increased DNA 5-hydroxymethylcytosine (5hmC) modification, and in turn, activated NFκB signaling. Notably, AML with TET2 mutations or chemotherapy resistance were highly sensitive to OPA1. Our results reveal a previously unknown OPRM1-TET2-5hmC-TRAF2 regulatory axis in AML, and suggest that opioid agonists, particularly OPA1, an FDA-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2 mutated and chemotherapy-resistant AML, which have a poor prognosis.
2024-01-19 | GSE165803 | GEO
Project description:By comparing the multi-omics profile of human NK cells before and after G-CSF in vivo treatment, we identified a pathway that was activated in response to G-CSF treatment, which suppressed IFN-γ secretion in NK cells. Specifically, integrative genomic strategy uncovered that glucocorticoid receptor (GR) was activated and mediated the genomic response to G-CSF treatment in NK cells. Activated GR can inhibit secretion of IFN-γ via promoting interactions between suppressor of cytokine signaling 1 (SOCS1) promoter and enhancer and increase the expression of SOCS1.
2022-09-30 | GSE183866 | GEO
Project description:Acute myeloid leukemia (AML) is a group of heterogeneous diseases with high malignancy. The ten-eleven translocation (TET) mediated DNA demethylation was known to be critically associated with AML pathogenesis. Through chemical compound screening, we found an opioid receptor agonist, namely loperamide hydrochloride (OPA1), most significantly suppressed AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, were then verified in AML cells in vitro, and AML mouse models carrying t(11q23) and t(8;21) in vivo. OPA1-induced activation of OPRM1 enhanced the transcription of TET2, increased DNA 5-hydroxymethylcytosine (5hmC) modification, and in turn, activated NFκB signaling. Notably, AML with TET2 mutations or chemotherapy resistance were sensitive to OPA1. Our results unveiled the previously unappreciated OPRM1-TET2-5hmC-TRAF2 regulatory axis in AML, and highlighted the therapeutic potential of opioid agonists, particularly OPA1, a FDA-approved antidiarrheal drug, in treating AML, especially TET2 mutated AML and chemotherapy-resistant AML, which were known to have poor prognosis.
2023-03-20 | GSE147510 | GEO
Project description:Acute myeloid leukemia (AML) is a group of heterogeneous diseases with high malignancy. The ten-eleven translocation (TET) mediated DNA demethylation was known to be critically associated with AML pathogenesis. Through chemical compound screening, we found an opioid receptor agonist, namely loperamide hydrochloride (OPA1), most significantly suppressed AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, were then verified in AML cells in vitro, and AML mouse models carrying t(11q23) and t(8;21) in vivo. OPA1-induced activation of OPRM1 enhanced the transcription of TET2, increased DNA 5-hydroxymethylcytosine (5hmC) modification, and in turn, activated NFκB signaling. Notably, AML with TET2 mutations or chemotherapy resistance were sensitive to OPA1. Our results unveiled the previously unappreciated OPRM1-TET2-5hmC-TRAF2 regulatory axis in AML, and highlighted the therapeutic potential of opioid agonists, particularly OPA1, a FDA-approved antidiarrheal drug, in treating AML, especially TET2 mutated AML and chemotherapy-resistant AML, which were known to have poor prognosis.
2023-03-20 | GSE147509 | GEO
Project description:Acute myeloid leukemia (AML) is a type of heterogeneous and fatal hematopoietic malignancy. The ten-eleven translocation (TET) mediated DNA demethylation is known to be critically associated with AML pathogenesis. Through chemical compound screening, we found that the opioid receptor agonist, loperamide hydrochloride (OPA1), significantly suppresses AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, were then verified in AML cells in vitro, and t(11q23) and t(8;21) AML mouse models in vivo. OPA1-induced activation of OPRM1 enhanced the transcription of TET2, increased DNA 5-hydroxymethylcytosine (5hmC) modification, and in turn, activated NFκB signaling. Notably, AML with TET2 mutations or chemotherapy resistance were highly sensitive to OPA1. Our results reveal a previously unknown OPRM1-TET2-5hmC-TRAF2 regulatory axis in AML, and suggest that opioid agonists, particularly OPA1, an FDA-approved antidiarrheal drug, have therapeutic potential in AML, especially in TET2 mutated and chemotherapy-resistant AML, which have a poor prognosis.
2024-01-19 | GSE165650 | GEO
Project description:We generated Multiome RNA+ATAC data from the same cell from human PBMC. This served as a gold benchmark for a novel integration method for multi-omics data that we developed.
2021-12-02 | E-MTAB-11225 | biostudies-arrayexpress
Project description:We generated Multiome RNA+ATAC data from the same cell from human PBMC. This served as a gold benchmark for a novel integration method for multi-omics data that we developed.
2021-12-02 | E-MTAB-11226 | biostudies-arrayexpress
Project description:The androgen receptor (AR) has been linked to bladder cancer (BCa) progression, but if this involves circular RNAs (circRNAs) remains unclear. Here, we find that AR alters the levels of circRNA-FNTA (circFNTA) to increase BCa cell invasion and chemo-resistance. Mechanistically, AR represses the RNA editing gene ADAR2 via direct binding to its 5' promoter region to increase circFNTA levels, which then sponges the microRNA miR-370-3p to increase the expression of its host gene FNTA. This AR-mediated ADAR2/circFNTA/miR-370-3p/FNTA pathway then activates KRAS signaling to alter BCa cell invasion and chemo-sensitivity to cisplatin. A clinical BCa sample survey shows that circFNTA expression is elevated in BCa tissues, and results from a BCa mouse model indicate that depletion of circFNTA leads to the suppression of BCa metastases and increased cisplatin chemo-sensitivity. Together, based on our results using multiple BCa cell lines and an in vivo mouse model we suggest that targeting this newly identified AR/ADAR2/circFNTA/miR-370-3p/FNTA/KRAS axis may lead to the development of therapies to suppress BCa metastasis and to increase its chemo-sensitivity.
| S-EPMC7132336 | biostudies-literature