Phagosome-mediated anti-bacterial immunity is governed by the proton-activated chloride channel in peritoneal macrophages
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ABSTRACT:
PROVIDER: PRJNA1068182 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR27702617_1.fastq.gz | Fastqsanger.gz | |||
| SRR27702617_2.fastq.gz | Fastqsanger.gz | |||
| SRR27702622_1.fastq.gz | Fastqsanger.gz | |||
| SRR27702622_2.fastq.gz | Fastqsanger.gz |
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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.
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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.
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Project description:Phagosome degradation is an evolutionally conserved and highly effective innate immune response against pathogen infections. The success of this process relies on the ability of phagocytes to regulate the maturation of phagosomes. However, the underlying molecular mechanisms and its roles in shaping downstream immune activation remain poorly understood. Here, we identify the proton-activated chloride (PAC) channel as a key negative regulator of phagosome maturation. PAC deletion enhanced phagosomal acidification and protease activities, leading to augmented bacterial killing in large peritoneal macrophages (LPMs) upon peritoneal Escherichia coli infection in mice. Surprisingly, phagosome bacterial degradation also stimulated STING-IRF3-interferon responses and inflammasome activation in LPMs, both of which are enhanced upon PAC deletion. The increased inflammasome activation and pyroptosis induced an unexpected release of cleaved gasdermin D, which localized to the surface of bacteria in the peritoneum and further contributed to their killing. Finally, enhanced bacterial clearance by PAC-deficient LPMs reduced proinflammatory immune cell infiltration and overall peritoneal inflammation, resulting in improved survival in mice. Our study thus provides new insights into the molecular mechanism of phagosome maturation and the dynamics of host defense response following phagosome-mediated bacterial degradation in peritoneal macrophages. It also highlights the potential of targeting the PAC channel as a therapeutic strategy for treating bacterial infections.
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