ABCG2 is an itaconate exporter that limits TFEB-mediated lysosomal biogenesis to impair antibacterial innate immunity
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ABSTRACT:
PROVIDER: PRJNA937205 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23565913_1.fastq.gz | Fastqsanger.gz | |||
| SRR23565913_2.fastq.gz | Fastqsanger.gz | |||
| SRR23565914_1.fastq.gz | Fastqsanger.gz | |||
| SRR23565914_2.fastq.gz | Fastqsanger.gz | |||
| SRR23565915_1.fastq.gz | Fastqsanger.gz |
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Project description:Itaconate is an immunoregulatory metabolite produced by the mitochondrial enzyme immune-responsive gene 1 (IRG1) in inflammatory macrophages. We recently identified an important mechanism by which itaconate is released from inflammatory macrophages. However, it remains unknown whether extracellular itaconate is taken up by non-myeloid cells to exert immunoregulatory functions. Here, we used a custom-designed CRISPR screen to identify the dicarboxylate transporter solute carrier family 13 member 3 (SLC13A3) as an itaconate importer and to characterize the role of SLC13A3 in itaconate-improved hepatic antibacterial innate immunity. Functionally, liver-specific deletion of Slc13a3 impairs hepatic antibacterial innate immunity in vivo and in vitro. Mechanistically, itaconate uptake via SLC13A3 induces transcription factor EB (TFEB)-dependent lysosomal biogenesis and subsequently improves antibacterial innate immunity in murine hepatocytes. These findings identify SLC13A3 as a key itaconate importer in murine hepatocytes and will aid in the development of potent itaconate-based antibacterial therapeutics.
2024-07-08 | GSE230735 | GEO
Project description:Itaconate is a metabolite that synthesized from cis-aconitate in mitochondria and transported into cytosol to exert multiple regulatory effects in macrophages. However, the mechanism by which itaconate exits from the cytosol of activated macrophages remains unknown. Using a genetic screen, we reveal that cytosolic itaconate is exported by ABCG2, an ATP-binding cassette (ABC) transporter, in an ATPase-dependent manner in human and mouse macrophages.
2024-05-01 | GSE225712 | GEO
Project description:Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity
| PRJNA962479 | ENA
Project description:Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with many human diseases, such as lysosomal storage disorders (LSD). How the cell detects lysosomal defects and then restores lysosomal function remain incompletely understood. Here, we show that STING mediates a common neuroinflammatory gene signature in three distinct lysosomal storage disorders, Galctwi/twi, Ppt1-/-, and Cln7-/-. Transcriptomic analysis of Galctwi/twi brain tissue revealed that STING also mediates the expression of a broad panel of lysosomal genes that are part of the CLEAR (Coordinated Lysosomal Expression and Regulation) signaling pathway, which is regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-seq analysis show that STING regulates lysosomal gene expression in microglia in LSD mice. Mechanistically, we show that STING activation in both human and mouse cells leads to TFEB dephosphorylation, nuclear translocation, and expression of target lysosomal genes. In addition, STING-mediated TFEB activation requires its proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Functionally, we show that the STING-proton channel-TFEB axis plays a role in facilitating lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control and recovery mechanism that responds to both genetic and chemically induced lysosomal dysfunction.
2025-04-23 | GSE283768 | GEO
Project description:Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy with critical roles in several cancers. Lysosomal autophagy promotes cancer survival through degradation of toxic molecules and maintenance of adequate nutrient supply. Doxorubicin (DOX) is the standard of care treatment for triple-negative breast cancer (TNBC); however, chemoresistance at lower doses and toxicity at higher doses limit its usefulness. By targeting pathways of survival, DOX can become an effective antitumor agent. In this study, we examined the role of TFEB in TNBC and its relationship with autophagy and DNA damage induced by DOX. In TNBC cells, TFEB was hypo-phosphorylated and localized to the nucleus upon DOX treatment. TFEB knockdown decreased the viability of TNBC cells while increasing caspase-3 dependent apoptosis. Additionally, inhibition of TFEB-phosphatase calcineurin sensitized cells to DOX-induced apoptosis in a TFEB dependent fashion. Regulation of apoptosis by TFEB was not a consequence of altered lysosomal function, as TFEB continued to protect against apoptosis in the presence of lysosomal inhibitors. RNA-Seq analysis of TFEB knockdown MDA-MB-231 cells identified a significant downregulation in cell cycle and homologous recombination while genes involved in interferon-γ and TNFα signaling were upregulated. In consequence, knockdown of TFEB was found to disrupt DNA repair following DOX, as evidenced by persistent γH2A.X detection. Together, these findings describe in TNBC a novel lysosomal independent function for TFEB in responding to DNA damage.
2020-12-22 | GSE139203 | GEO
Project description:Transcription factor EB (TFEB), well characterized as a master regulator of autophagy and lysosomal biogenesis, is translocated to the nucleus and activated by varieties of cellular stresses including starvation and lysosomal damage. However, compared to the starvation condition, the molecular mechanism of TFEB activation by other stress conditions is poorly understood. Previously, we have shown that TFEB activation during lysosomal damage but not starvation condition depends on a subset of autophagy regulators, collectively called ATG conjugation system, whose function is essential for the lipidation of ATG8 proteins. In this study, by time-lapse imaging, we newly identified the presence of ATG conjugation system -independent TFEB regulation which precedes the ATG conjugation system-dependent regulation, designated mode I and mode II, respectively. Consistent with the presence of different modes, our time course transcriptome analysis revealed two different sets of TFEB downstream. Comprehensive interactome analysis of TFEB and subsequent functional screening identified unique regulars of TFEB in each mode: APEX1 for Mode I and CCT7 and/or TRIP6 for Mode II, respectively. APEX1 interacted with TFEB and was required for its protein stability in a manner independent of ATG conjugation system. On the other hand, both CCT7 and TRIP6 were accumulated on lysosomes during lysosomal damage and interacted with TFEB mainly in ATG conjugation system deficient cells, presumably blocking TFEB nuclear translocation. Moreover, we further revealed that TFEB regulatory mechanisms by other cellular stresses such as oxidative stress, proteasome inhibition, mitochondria depolarization, and DNA damage can be classified into either APEX1-mediated Mode I or TRIP6-mediated Mode II. Our results pave the way for a unified understanding TFEB regulatory mechanisms from the perspective of ATG conjugation system under varieties of cellular stresses.
2025-01-31 | GSE235340 | GEO
Project description:The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. We identify a distinct nuclear interactome of TFEB, with USP7 emerging as a key post-translational modulator of TFEB. Genetic depletion and inhibition of USP7 reveal its critical role in preserving TFEB stability within both nuclear and cytoplasmic compartments. Specifically, USP7 is identified as the deubiquitinase responsible for removing the K48-linked polyubiquitination signal from TFEB at lysine residues K116, K264, and K274, thereby preventing its proteasomal degradation. Functional assays demonstrate the involvement of USP7 in preserving TFEB-mediated transcriptional responses to nutrient deprivation, while also modulating autophagy flux and lysosome biogenesis. As USP7 is a deubiquitinase that protects TFEB from proteasomal degradation, these findings provide the foundation for therapeutic targeting of the USP7-TFEB axis in conditions characterized by TFEB dysregulation and metabolic abnormalities, particularly in certain cancers.
2024-09-17 | PXD055937 | Pride
Project description:STING1 is an essential component of the innate immune defense against a wide variety of pathogens. Whereas induction of Type I interferon (IFN) responses is one of the best-defined functions of STING1, our transcriptomic analysis revealed IFN-independent activities of STING1 in macrophages, including transcriptional upregulation of numerous lysosomal and autophagic genes. This upregulation was mediated by the STING1-induced activation of the transcription factors TFEB and TFE3, and led to increased autophagy, lysosomal biogenesis, and lysosomal acidification. TFEB and TFE3 also modulated IFN-dependent STING1 signaling by controlling IRF3 activation. IFN production and cell death were increased in TFEB and TFE3 depleted iBMDMs. Conversely, TFEB over-expression led to reduced IRF3 activation and an almost complete inhibition of interferon synthesis and secretion, resulting in decrease caspase-3 activation and increased cell survival. Our study reveals a key role of TFEB and TFE3 as regulators of STING1-mediated innate antiviral immunity.
2025-04-08 | GSE281183 | GEO
Project description:Cells experience oxidative stress and widespread cellular damage during stress-induced premature senescence (SIPS). Senescent cells are characterized by an increase in lysosomal content, which may contribute to mitigating cellular damage by promoting autophagy. This study investigates the dynamics of lysosomal quality control in human dermal fibroblasts (HDF), specifically examining lysosomal signaling pathways during oxidative stress-induced SIPS. Our results reveal distinct signaling responses between the initial stress phase and the ensuing senescent phenotype. During the stress phase, treatment with tBHP, which undermines the antioxidant response, results in an escalation of lysosomal damage. Increased ROS levels trigger activation of AMP-activated protein kinase (AMPK) and inactivation of Akt, leading to suppression of mammalian target of rapamycin (mTOR). Inactivation of mTOR during this phase facilitates the activation of transcription factor EB (TFEB), a key player in modulating ROS levels, enhancing autophagy, and enabling cellular survival. Interestingly, TFEB knockdown cells under stress exhibited increased apoptosis, highlighting the protective role of TFEB in the stress response. As cells enter senescence, TFEB activity, required for the autophagic damage repair becomes less critical. The decrease in ROS levels leads to the normalization of AMPK and Akt signaling, resulting in reactivation of mTOR. This reactivation of mTOR, which is critical for establishing the senescent state, mediates the inactivation of TFEB. Consequently, as damage decreases, TFEB activity decreases. Our results reveal a dynamic interplay between TFEB and mTOR, highlighting a critical role of TFEB in modulating cellular fate during the transition from stress response to senescence and postulates TFEB activation as a potential senomorphic treatment.
2025-03-02 | GSE290476 | GEO
Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1β-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages. Experiment 1: mature WT BMDM were treated for 12h with 0.25 mM dimethyl itaconate (DI) or vehicle (Unst) and then stimulated with LPS (E. coli 0111:B4; 100 ng/ml, 4h) (DI+LPS; LPS); Experiment 2: mature Irg1-/- BMDM were stimulated with LPS (E. coli 0111:B4; 100 ng/ml) and murine recombinant IFNg (50 ng/ml) for 24h.
2016-07-01 | E-GEOD-82043 | biostudies-arrayexpress