LITAF regulation of cell death and inflammatory responses

点击翻译按钮获取中文摘要

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.