Identification of acidic extracellular pH-modulated genes
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ABSTRACT:
PROVIDER: PRJNA1154953 | ENA |
REPOSITORIES: ENA
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Project description:To investigate the genes that are modulated by acidic extracellular pH, we treated the mouse B16-BL6 cells with acidic medium and then analyzed them comprehensively by cDNA microarray.
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2014-07-07 | GSE52020 | GEO
Project description:Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin (IL)-2, a critical cytokine in T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation and anti-tumor immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Ra with higher affinity, triggers STAT5 activation and drives CD8+ T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Finally, we find that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.
2022-12-02 | GSE213440 | GEO
Project description:Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin (IL)-2, a critical cytokine in T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation and anti-tumor immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Ra with higher affinity, triggers STAT5 activation and drives CD8+ T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Finally, we find that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.
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Project description:The conditions of the tumor microenvironment, such as hypoxia and nutrient starvation, play critical roles in cancer progression. However, the role of acidic extracellular pH in cancer progression is not studied as extensively as that of hypoxia. Here, we show that extracellular acidic pH (pH 6.8) triggered activation of sterol regulatory element-binding protein 2 (SREBP2) by stimulating nuclear translocation and promoter binding to its targets along with intracellular acidification. Interestingly, inhibition of SREBP2, but not SREBP1, suppressed the upregulation of low pH-induced cholesterol biosynthesis-related genes. Moreover, acyl-CoA synthetase short-chain family member 2 (ACSS2), a direct SREBP2 target, provided a growth advantage to cancer cells under acidic pH. Furthermore, acidic pH-responsive SREBP2 target genes were associated with reduced overall survival of cancer patients. Thus, our findings show that SREBP2 is a key transcriptional regulator of metabolic genes and progression of cancer cells, partly in response to extracellular acidification.
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Project description:The purpose of this study was to examine how Mtb integrates acidic pH and available carbon sources as environmental cues to regulate its metabolism and growth rate. RNA-seq transcriptional profiling of M. tuberculosis growing at acidic or neutral pH, in pyruvate or glycerol, was examined. These studies identified carbon source-dependent and -independent pH-dependent adaptations. Mtb strain CDC1551 was grown in standing T-75 flasks in 40 mL of medium seeded an initial OD of 0.1. We examined medium in four conditions pH 7.0 10 mM glycerol, pH 5.7 10 mM glycerol, pH 7.0 10 mM pyruvate, pH 5.7 10 mM pyruvate. Following 3 days of incubation at 37C, RNA was isolated from the bacterial cultures and used for RNA-seq.
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Project description:Human cells require pH regulation to maintain physiological function, yet the molecular consequences of acidic environments remain incompletely understood. Here, we employ a gas-only bioreactor to control pH, oxygen, and temperature. Integrated Omics analyses reveal that acidic pH induces a glycolytic metabolic shift, suppresses proliferation, and promotes accumulation of lactate and oncometabolites alongside mitochondrial dysfunction. Acidic conditions increase reactive oxygen species (ROS) and activate inflammatory and immune pathways, leading to heteroplasmic enrichment of a pathogenic mitochondrial mutation. Acidic pH depletes intracellular NAD⁺, partly driven by PARP1 activation. Restoring NAD⁺ through nicotinamide mononucleotide (NMN) supplementation partially rescues proliferation and stress-associated transcription, while elevating NAD+ levels by NMN or PARP1 inhibition reverses heteroplasmic enrichment of mutant mitochondrial DNA. These findings underscore the role of pH homeostasis in coordinating metabolism, redox balance, and immune signaling, and identify NAD⁺ metabolism as a mechanistic link between acidic microenvironments, mitochondrial genome instability, and immune–metabolic remodeling.
2026-03-11 | GSE254130 | GEO
Project description:Human cells require precise pH regulation to maintain optimal physiological functions, yet the molecular impacts of acidic environments remain underexplored due to the lack of technologies capable of precisely controlling the cell culture environment. Here, we employed a gas-only bioreactor to stably control pH, dissolved oxygen, and temperature during the culture of human B lymphoblastoid cells. Integrated transcriptomic, epigenomic, and metabolomic analysis revealed that acidic pH (6.8) induces a metabolic shift towards glycolysis, suppresses energy-intensive processes such as cell proliferation, and triggers intracellular accumulation of lactate and oncometabolites and mitochondrial dysfunction. This environment also elevates reactive oxygen species (ROS) and upregulates inflammatory and immune pathways, leading to heteroplasmic shifts in a pathogenic mitochondrial mutation. Mechanistically, acidic pH caused marked depletion of intracellular NAD⁺ driven in part by PARP1 activation, and restoration of NAD⁺ levels via nicotinamide mononucleotide supplementation or PARP1 inhibition partially rescued cellular proliferation, mitochondrial genomic integrity, and stress-associated transcriptional programs. These findings highlight the critical role of pH homeostasis in cellular metabolism and immune response, offering insights into the cellular adaptations to acidic stress, which may inform therapeutic strategies for conditions like cancer and metabolic disorders.
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Project description:The purpose of this study was to identify genes that are differentially expressed upon prrA overexpression, to reveal the impact of PrrA on global transcription in acidic pH and/or high chloride conditions.
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