LITAF regulation of cell death and inflammatory responses

LITAF 调节细胞死亡和炎症反应

• 批准号: 10886166
• 负责人: Adam Lacy-Hulbert
• 金额: $ 29.96万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10886166
• 关键词: Affect; Applications Grants; Bacterial Infections; Biochemical; Cell Death; Cell Death Induction; Cell Survival; Cell membrane; Cell model; Cells; Cellular Stress; Cellular biology; Cessation of life; Clustered Regularly Interspaced Short Palindromic Repeats; Communicable Diseases; Data; Defense Mechanisms; Disease; Epithelial Cells; Epithelium; Equilibrium; Genes; Genetic Screening; Hemolysin; High-Throughput DNA Sequencing; Homeostasis; Host Defense; Immune; Immune signaling; Immunity; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Link; Lung; Lung infections; Macrophage; Mechanics; Mediating; Membrane; Membrane Proteins; Mission; Molecular Biology; Mus; Mutagenesis; Mutation; Nutrient; Pathologic; Pathology; Pathway interactions; Play; Pneumonia; Production; Pulmonary Inflammation; RNA Interference; Regulation; Reporting; Research; Resistance; Role; Signal Transduction; Staphylococcus aureus; Staphylococcus aureus infection; Stress; System; Testing; Toxin; United States National Institutes of Health; VDAC1 gene; Vesicle; airway epithelium; alpha Toxin; cell injury; cytokine; exosome; experimental study; human model; in vivo; in vivo Model; inhibitor; lung injury; monocyte; mouse model; overexpression; pathogen; pathogenic bacteria; prevent; repaired; response; screening; ubiquitin ligase

Project Summary Membrane damage by mechanical or biochemical stress, leads to cell death and activation of innate immune inflammatory pathways, and contributes to the pathology of many inflammatory conditions. Furthermore, pathogens can secrete pore-forming toxins (PFT) to promote infection and disrupt immunity, and endogenous pore-forming proteins such as Gasdermin D and MLKL have been shown to contribute to inflammatory signaling and secretion of cytokines. Cells have evolved multiple mechanisms to repair membrane damage and maintain cellular homeostasis, but our understanding of how damage is sensed and linked to repair remains incomplete. We have recently developed a transposon-based forward genetic screening approach, which we have used to identify genes that promote resistance to cell death induced by S. aureus α-toxin. We identified the lysosomal membrane protein LITAF as a cell-autonomous inhibitor of cell death. In preliminary data, we show that LITAF promotes sequestration of damaged membranes into vesicles through the activation of the ESCRT machinery. We hypothesize that LITAF acts as an effector of cellular defense against pore-forming proteins, linking sensing of membrane damage to effector mechanisms of repair. In this application, we propose to test this hypothesis by: (1) identifying the mechanisms of LITAF activation and function; (2) determining the role of this pathway in lung inflammation and infection; (3) testing whether LITAF regulates innate immune signaling, inflammasome activation and inflammatory cell death in macrophages. This research is of high significance as it will provide a deeper understanding of cellular defense mechanisms against membrane damage, and of the balance between cell survival and inflammatory cell death. Identifying strategies to counteract membrane damage and prevent cell death will contribute to understanding and treating the pathology of a wide range of infectious and inflammatory diseases.

项目总结