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STING-mediated proton channel activity, signaling, and autoinflammatory disease require ArfGAP2 [Jurkat]

ABSTRACT: STING-mediated proton channel activity, signaling, and autoinflammatory disease require ArfGAP2 [Jurkat]

PROVIDER: PRJNA1193602 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31589152_1.fastq.gz	Fastqsanger.gz
	SRR31589152_2.fastq.gz	Fastqsanger.gz
	SRR31589153_1.fastq.gz	Fastqsanger.gz
	SRR31589153_2.fastq.gz	Fastqsanger.gz
	SRR31589154_1.fastq.gz	Fastqsanger.gz

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STING-mediated proton channel activity, signaling, and autoinflammatory disease require ArfGAP2 [Jurkat]

Project description:STING transmits signals downstream of the cytosolic DNA sensor cGAS, leading to transcriptional up-regulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (SAVI) mice. Recent discoveries revealed that STING also functions as a proton channel that deacidifies the Golgi. Since pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.

2024-12-31 | GSE283416 | GEO

STING-mediated proton channel activity, signaling, and autoinflammatory disease require ArfGAP2 [BMDM]

2024-12-31 | GSE283415 | GEO

STING-mediated proton channel activity, signaling, and autoinflammatory disease require ArfGAP2 [BMDM]

Project description:STING-mediated proton channel activity, signaling, and autoinflammatory disease require ArfGAP2 [BMDM]

| PRJNA1193600 | ENA

STING-mediated proton channel activity, signaling, and autoimmune disease require ArfGAP2

Project description:STING transmits signals downstream of the cytosolic DNA sensor cGAS, leading to transcriptional up-regulation of cytokines. However, components of the STING signaling pathway, such as IRF3 and IFNAR1, are not essential for autoinflammatory disease in STING gain-of-function (SAVI) mice. Recent findings indicate that STING can also function as a proton channel that deacidifies the Golgi. Since pH impacts Golgi enzyme activity, protein maturation, and trafficking, we hypothesized that STING proton channel activity influences multiple Golgi functions. Here, we show that STING-mediated proton efflux non-transcriptionally regulates Golgi trafficking of protein cargos. This process requires the Golgi-associated protein ArfGAP2, a cell type-specific dual regulator of STING-mediated proton efflux and signaling. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Thus, ArfGAP2 facilitates STING-mediated signaling and cytokine release in hematopoietic cells, significantly contributing to autoinflammatory disease pathogenesis.

2024-11-30 | PXD058416 | Pride

STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation

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

STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation

Project description:STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation

| PRJNA1195557 | ENA

Genetics and Pathophysiology of Autoinflammatory Disorders

Project description:Genetics and Pathophysiology of Autoinflammatory Disorders

| PRJNA552920 | ENA

Genetics and Pathophysiology of Autoinflammatory Disorders

Project description:Genetics and Pathophysiology of Autoinflammatory Disorders

| PRJNA552921 | ENA

Jurkat T cells

Project description:Jurkat T cells

| PRJNA958225 | ENA

Cellular and Neural Responses to Sour Stimuli Require the Proton Channel Otop1.

Project description:The sense of taste allows animals to sample chemicals in the environment prior to ingestion. Of the five basic tastes, sour, the taste of acids, had remained among the most mysterious. Acids are detected by type III taste receptor cells (TRCs), located in taste buds across the tongue and palate epithelium. The first step in sour taste transduction is believed to be entry of protons into the cell cytosol, which leads to cytosolic acidification and the generation of action potentials. The proton-selective ion channel Otop1 is expressed in type III TRCs and is a candidate sour receptor. Here, we tested the contribution of Otop1 to taste cell and gustatory nerve responses to acids in mice in which Otop1 was genetically inactivated (Otop1-KO mice). We first show that Otop1 is required for the inward proton current in type III TRCs from different parts of the tongue that are otherwise molecularly heterogeneous. We next show that in type III TRCs from Otop1-KO mice, intracellular pH does not track with extracellular pH and that moderately acidic stimuli do not elicit trains of action potentials, as they do in type III TRCs from wild-type mice. Moreover, gustatory nerve responses in Otop1-KO mice were severely and selectively attenuated for acidic stimuli, including citric acid and HCl. These results establish that the Otop1 proton channel plays a critical role in acid detection in the mouse gustatory system, evidence that it is a bona fide sour taste receptor.

| S-EPMC7299528 | biostudies-literature

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