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Molecular Insights into the Inhibition of Proton-Activated Chloride Channel by Transfer RNA

ABSTRACT: Molecular Insights into the Inhibition of Proton-Activated Chloride Channel by Transfer RNA

PROVIDER: PRJNA896180 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29437353.fastq.gz	Fastqsanger.gz
	SRR29407596.fastq.gz	Fastqsanger.gz

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Molecular Insights into the Inhibition of Proton-Activated Chloride Channel by Transfer RNA

Project description:The proton-activated chloride (PAC) channel (also known as acid-sensitive outwardly rectifying anion channel, ASOR) plays a critical role in acid-induced cell death and endocytosis. However, little is known about the regulatory factors and binding partners of PAC. In this study, we discovered that transfer RNA (tRNA) interacts directly with PAC as an unexpected binding partner. Using cryo-electron microscopy, we determined that two PAC trimers and one co-purified tRNA molecule form a stable complex via a highly conserved KR motif, representing the closed conformation. tRNA is located on the intracellular side of PAC, blocking the channel pores. Furthermore, electrophysiological data showed that tRNA modulates chloride currents and channel open probability of PAC, thus protecting against acid-induced cell death. Our study provides insight into the regulation of PAC activity by cytosolic tRNA and extends the role of tRNAs in pathological and physiological events.

2024-06-28 | GSE216637 | GEO

Phagosome-mediated anti-bacterial immunity is governed by the proton-activated chloride channel in peritoneal macrophages

Project description:Phagosome-mediated degradation is a well-conserved and highly effective innate immune response against pathogen infections. However, its role in shaping immune responses remains underappreciated. The molecular mechanisms underlying how phagosomes mature are also poorly understood. Here, we identify proton-activated chloride (PAC) channel as a key negative regulator of phagosome maturation. PAC deletion facilitates phagosomal acidification and protease activation, leading to augmented bactericidal activity in peritoneal macrophages upon Escherichia coli infection. Moreover, enhanced phagosome bacterial degradation in PAC-deficient macrophages promotes downstream STING-IRF3 activation and type 1 interferon (IFN) responses through the release of bacterial ligands. Such ligand release also activates the inflammasome, leading to gasdermin D (GSDMD) cleavage and secretion. The secreted N-terminus GSDMD directly participates in bacterial killing by forming GSDMD pores on bacterial surfaces. Eventually, this macrophage hyperactivation is terminated by pyroptotic cell death. In mice, PAC deletion in macrophages reduced overall peritoneal inflammation and proinflammatory neutrophil and monocyte infiltrations, as well as improved survival after peritoneal infection. Our study thus provides new insights into mechanisms of phagosome maturation and the dynamics of host defense response following phagosome-mediated bacterial degradation.

2025-06-09 | GSE254043 | GEO

Phagosome-mediated anti-bacterial immunity is governed by the proton-activated chloride channel in peritoneal macrophages

Project description:Phagosome-mediated anti-bacterial immunity is governed by the proton-activated chloride channel in peritoneal macrophages

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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.

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

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TMC4 is a novel chloride channel involved in high-concentration salt taste sensation

Project description:Taste substances are received by taste receptors expressed in taste cells. “Salty taste” sensation is evoked when sodium and chloride ions are present together in the oral cavity. The presence of an epithelial cation channel that receives Na+ has previously been reported. However, no molecular entity involving Cl- receptors has been elucidated. We report the strong expression of transmembrane channel-like 4 (TMC4) in the circumvallate and foliate papillae projected to the glossopharyngeal nerve, mediating a high-concentration of NaCl. Electrophysiological analysis using HEK293T cells revealed that TMC4 was a voltage-dependent Cl- channel and the consequent currents were completely inhibited by NPPB, an anion channel blocker. This channel could be activated without an increase in intracellular calcium ion. TMC4 allowed permeation of organic anions including gluconate, but their current amplitudes at positive potentials were less than that of Cl-. Tmc4-deficient mice showed significantly weaker glossopharyngeal nerve response to high-concentration of NaCl than the wild-type littermates. These results indicated that TMC4 is a novel chloride channel that responds to high-concentration of NaCl.

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

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2024-11-30 | PXD058416 | Pride

Expression data from "sensitized" mice exposed via respiratory tract to chemical (methylene diphenyldiisocyanate)-glutathione conjugates +/- chloride channel inhibitor (crofelemer)

Project description:Methylene diphenyl diisocyanate is a chemical known to cause asthma. The present study uses mice to investigate exposure-induced changes in lung gene expression and effects of a chloride channel inhibitor We used microarrays to detail global whole lung gene expression following respiratory tract exposure to methylene diphenyl diisocyanate (MDI) vs. control exposure in mice immune-sensitized to MDI by prior skin exposure. In some studies mice were given a chloride channel inhibitor (crofelemer) via the respiratory tract before MDI.

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Endosomal chloride/proton exchangers need inhibitory TMEM9 β-subunits for regulation and prevention of disease-causing overactivity

Project description:Multi-epitope affinity purification mass spectrometry (meAP-MS) analysis of TMEM9-, TMEM9B- and CLC3- associated proteins from solubilized mouse brain membranes identified chloride channel subtypes CLCN3, 4 and 5 as exclusive interaction partners of TMEM9 and TMM9B.

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CLCN2 Chloride Channel Mutations in Familial Hyperaldosteronism Type II

Project description:CLCN2 Chloride Channel Mutations in Familial Hyperaldosteronism Type II

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