Lysosomal quality control through lipid remodeling

通过脂质重塑进行溶酶体质量控制

• 批准号: 10711028
• 负责人: Xiaojun Tan
• 金额: $ 39.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711028
• 关键词: 1-Phosphatidylinositol 4-Kinase; Aging; Cardiovascular Diseases; Cell Death; Cell Membrane Permeability; Cell model; Cell physiology; Cellular Stress; Chemicals; Cholesterol; Disease; Endoplasmic Reticulum; FDA approved; Family member; Functional disorder; Homeostasis; Human; Lipids; Lysosomal Storage Diseases; Lysosomes; Mediating; Membrane; Nerve Degeneration; Nutrient; Pathway interactions; Phosphatidylinositols; Phosphatidylserines; Play; Production; Protein Family; Proteins; Proteomics; Quality Control; Recycling; Role; Therapeutic; cell growth; design; human disease; improved; interest; lipid transport; lipidomics; oxysterol binding protein; phosphatidylinositol 4-phosphate; recruit; repaired; response; small molecule; small molecule libraries; stressor

Project Summary/Abstract: Lysosomes play essential roles in cell physiology, not only controlling nutrient recycling and cellular growth, but also mediating the proper handling of various cellular stress. Lysosomal dysfunction is associated with aging and many diseases such as lysosomal storage disease, neurodegeneration, and cardiovascular diseases. A hallmark of lysosomal-related diseases is lysosomal membrane permeabilization/damage (LMP) which if not immediately resolved can cause detrimental problems including cell death. We now start to understand that LMP triggers multiple cellular pathways to repair damaged lysosomes. However, none of the previously described pathways appear to be essential for rapid lysosomal repair, suggesting additional repair mechanisms. As an attempt to find such mechanism, we recently designed and executed an unbiased proteomic screen searching for proteins specifically enriched on damaged lysosomes. This screen led to the discovery of the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway as an essential mechanism for rapid lysosomal repair. We found that LMP stimulates robust production of phosphatidylinositol-4-phosphate (PtdIns4P, PI4P) on damaged lysosomes by type II alpha phosphatidylinositol-4 kinase (PI4K2A). Lysosomal PI4P drives the formation of extensive membrane contacts between the endoplasmic reticulum (ER) and damaged lysosomes by recruiting multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members. The ORPs catalyze subsequent ER-to-lysosomal transport of cholesterol and phosphatidylserine (PS) to mediate rapid membrane repair. While cholesterol by itself increases membrane stability, PS activates ATG2-mediated lipid transport for direct lysosomal repair. The PITT pathway is activated in response to diverse disease-related lysosomal-damaging conditions and is expected to have enormous impact on human pathophysiology. Remarkably, the PITT pathway not only reveals lipid transfer at membrane contacts as a essential mechanism for lysosomal repair, but it also establishes lipid remodeling as a new platform to understand lysosomal quality control. Through three independent projects in the next five years, our lab will continue studying LMP-triggered lysosomal lipid remodeling for better mechanistic understanding of lysosomal quality control and potential therapeutic applications. First, we are purifying lysosomes during and after lysosomal repair to characterize lipid changes by lipidomics, which we believe will identify new lipid messengers important for lysosomal quality control. Second, the PITT-mediated lysosomal cholesterol accumulation provides a great cellular model to study cholesterol transport, and we are particularly interested in the mechanism for cholesterol egress from newly repaired lysosomes. Finally, we are also performing chemical screens using FDA- approved chemical library to search for small molecules that activate or block the PITT pathway. The identified small molecules have well established protein targets, which will help define the regulatory networks for the PITT lysosomal quality control pathway as well as delineate new strategies to improve lysosomal quality.

项目总结/文摘:

项目成果

A conserved ion channel function of STING mediates noncanonical autophagy and cell death.

STING 的保守离子通道功能介导非典型自噬和细胞死亡。

• DOI: 10.1038/s44319-023-00045-x
• 发表时间: 2024
• 期刊: EMBO reports
• 影响因子: 7.7
• 作者: Xun,Jinrui;Zhang,Zhichao;Lv,Bo;Lu,Defen;Yang,Haoxiang;Shang,Guijun;Tan,JayXiaojun
• 通讯作者: Tan,JayXiaojun