Ontology highlight
ABSTRACT:
PROVIDER: PRJNA369731 | ENA |
REPOSITORIES: ENA
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Project description:Immune checkpoint inhibitor (ICI) therapies are associated with an increased risk of metabolic syndrome; the underlying mechanisms remain elusive. We show here that anti-PD-1 antibody targets macrophage PD-1 to reduce energy expenditure without affecting food intake, leading to an augmented susceptibility of mice to high-fat diet (HFD)-induced obesity, and systemic metabolic disorders. Mechanistically, LPS activates Unc-51-like autophagy activating kinase 1 (ULK1) via Mechanistic target of rapamycin (mTOR)-dependent manner. Activated ULK1 phosphorylates PD-1 at Thr250 to inhibit FBXO38-mediated PD-1 ubiquitination and degradation by disrupting FBXO38-PD-1 binding. Phosphorylated PD-1 interacts with inositol-requiring enzyme 1α (IRE1α) and attenuates IRE1α autophosphorylation to suppress ER stress-mediated inflammatory responses. Inhibition or IRE1α knockout alleviates HFD-induced metabolic disorders in macrophage-specific PD-1 knockout mice by rescuing the reduced energy expenditure. Our findings highlight the critical role of macrophage PD-1 in the intersection of immune checkpoint blockade, energy expenditure, and metabolic dysfunction. The underscored moonlighting function of macrophage PD-1 in protecting against ER stress-driven systemic inflammation may provide new rational for combating both ICI therapy- and HFD-induced metabolic diseases.
2025-10-26 | GSE304734 | GEO
Project description:Cholera toxin (CT), a bacterial exotoxin composed of one A subunit (CTA) and five B subunits (CTB), functions as an immune adjuvant. CTB can induce production of interleukin-1β (IL-1β), a proinflammatory cytokine, in synergy with a lipopolysaccharide (LPS), from resident peritoneal macrophages (RPMs) through the pyrin and NLRP3 inflammasomes. However, how CTB or CT activates these inflammasomes in the macrophages has been unclear. Here, we clarified the roles of IRE1α , an endoplasmic reticulum (ER) stress sensor, in CT-induced IL-1β production from RPMs. In RPMs, CTB is incorporated into ER and induced ER stress responses, depending on GM1, a cell membrane ganglioside. IRE1α -deficient RPMs showed a significant impairment of CT- or CTB-induced IL-1β production, indicating that IRE1α was required for CT- or CTB-induced IL-1β production from RPMs. This study demonstrates the critical roles of IRE1α in activation of both NLRP3 and pyrin inflammasomes in tissue-resident macrophages.
2024-03-24 | GSE228915 | GEO
Project description:Gender differences in obesity is widely reported, however, identification of gender specific obese gene and characterization of its role in obesity remain elusive. Here, we identify a germ cell specifically expressed gene C2orf74 and demonstrate that C2ORF74 promotes high-fat diet (HFD) induced obesity in male but not female male. Loss of C2ORF74 protects male mice from obesity by boosting testosterone levels and enhancing energy expenditure and browning of white adipose tissues (WAT). We demonstrate that spermatogenic C2ORF74 suppresses testosterone biogenesis in Leydig cells through germ-cell secreted BPIFA3, whose maturation and secretion is dependent on DPM1-mediated glycosylation. Collectively, these findings define a role of spermatogenic C2ORF74 in energy expenditure and adipose browning in a gender specific manner.
2026-04-06 | GSE236434 | GEO
Project description:Gender differences in obesity is widely reported, however, identification of gender specific obese gene and characterization of its role in obesity remain elusive. Here, we identify a germ cell specifically expressed gene C2orf74 and demonstrate that C2ORF74 promotes high-fat diet (HFD) induced obesity in male but not female male. Loss of C2ORF74 protects male mice from obesity by boosting testosterone levels and enhancing energy expenditure and browning of white adipose tissues (WAT). We demonstrate that spermatogenic C2ORF74 suppresses testosterone biogenesis in Leydig cells through germ-cell secreted BPIFA3, whose maturation and secretion is dependent on DPM1-mediated glycosylation. Collectively, these findings define a role of spermatogenic C2ORF74 in energy expenditure and adipose browning in a gender specific manner.
2026-04-06 | GSE236432 | GEO
Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent and limiting side effect of paclitaxel treatment in cancer patients. CIPN affects sensory neurons through neuroinflammatory mechanisms, but how immune cells sense and interpret systemic paclitaxel exposure during treatment is unclear. Here, we report that paclitaxel administration triggers the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) in circulating and dorsal root ganglia-resident myeloid cells, engendering an inflammatory milieu that promotes CIPN. Mechanistically, paclitaxel induced overproduction of mitochondrial-derived reactive oxygen species (ROS) that provoked ER stress and IRE1α hyperactivation in macrophages. This process reprogrammed macrophages towards a highly inflammatory state characterized by IRE1α-dependent production of TNF-α, IL-1β, PGE2, IL-6, IL-5, GM-CSF, MCP-1, and MIP-2. Ablation of IRE1α in leukocytes, or treatment with a selective IRE1α pharmacological inhibitor, prevented dorsal root ganglia neuroinflammation and CIPN-related pain behaviors in mice. Furthermore, the development and severity of CIPN in patients with gynecological cancer was associated with the status of IRE1α activation in their circulating leukocytes. Our study uncovers leukocyte-intrinsic IRE1α as a key mediator of CIPN and suggests that targeting its dysregulated activation could help mitigate CIPN in cancer patients receiving paclitaxel.
2025-10-29 | GSE309119 | GEO
Project description:Cancer cells exploit adaptive responses such as endoplasmic reticulum (ER) stress to support their survival. ER stress response is mediated in part by the ER-localized transmembrane sensor IRE1α endoribonuclease and its substrate XBP1 to regulate XBP1 target gene expression. However, the mechanism that controls the IRE1α/XBP1 pathway remains poorly understood. CARM1 is an oncogene that is often overexpressed in a number of cancer types including ovarian cancer. Here we report that CARM1 determines ER stress response by controlling the IRE1α/XBP1 pathway. Genome-wide profiling revealed that CARM1 regulates XBP1 target gene expression during ER stress response. CARM1 directly interacts with XBP1. Inhibition of the IRE1α/XBP1 pathway was effective in ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model.
2021-08-11 | GSE157117 | GEO
Project description:Cancer cells exploit adaptive responses such as endoplasmic reticulum (ER) stress to support their survival. ER stress response is mediated in part by the ER-localized transmembrane sensor IRE1α endoribonuclease and its substrate XBP1 to regulate XBP1 target gene expression. However, the mechanism that controls the IRE1α/XBP1 pathway remains poorly understood. CARM1 is an oncogene that is often overexpressed in a number of cancer types including ovarian cancer. Here we report that CARM1 determines ER stress response by controlling the IRE1α/XBP1 pathway. Genome-wide profiling revealed that CARM1 regulates XBP1 target gene expression during ER stress response. CARM1 directly interacts with XBP1. Inhibition of the IRE1α/XBP1 pathway was effective in ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model.
2021-08-11 | GSE157116 | GEO
Project description:Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesized that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discovered that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impaired BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This was associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic.
2021-07-19 | GSE178366 | GEO
Project description:Endoplasmic reticulum (ER) stress signaling has been implicated in endothelial cell dysfunction and vascular diseases, but the transcriptional networks regulated by the ER stress sensor IRE1α in human endothelial cells remain incompletely defined. Here, we used RNA‑seq to profile the transcriptome of HUVECs following IRE1α knockdown. HUVECs were transfected with siRNA targeting IRE1α (siERN1) or a scramble control (siCtrl) for 48 h. Total RNA was extracted from three independent biological replicates per condition and subjected to stranded poly(A)-enriched RNA‑seq on an Illumina HiSeq platform, generating 125/150 bp paired‑end reads. Differential gene expression analysis identified transcripts significantly altered by IRE1α depletion. These data provide a resource for understanding IRE1α‑dependent gene regulation in endothelial cells and its potential role in vascular homeostasis and disease.
2026-09-01 | GSE331417 | GEO
Project description:This project investigates mechanisms underlying catecholamine resistance in obesity. We found that adipocyte Beta3-adrenergic receptor (Adrb3), the dominant isoform mediating lipolysis, undergoes transcriptional downregulation after ligand exposure or inflammatory stimulation, representing homologous and heterologous desensitization, respectively. Both processes are mediated by the EPAC-RAP2A-PI-PLC-TRIB1 signaling axis, which promotes degradation of the transcription factor C/EBP-alpha and suppresses Adrb3 expression. Pharmacologic inhibition of EPAC/RAP restored Beta3-adrenergic responsiveness, enhanced lipolysis, and improved energy expenditure in obese mice. These findings reveal a molecular pathway contributing to catecholamine resistance and impaired energy mobilization in obesity.
2026-01-07 | GSE315788 | GEO