ISGylation regulates lung endothelial inflammation

ISGylation 调节肺内皮炎症

• 批准号: 10394303
• 负责人: Yutong Zhao
• 金额: $ 53.42万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394303
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Anti-Inflammatory Agents; Cell Adhesion Molecules; Cell physiology; Data; Development; Disease; Endothelial Cells; Endothelium; Exhibits; F-Box Proteins; Family member; Foundations; Functional disorder; Genes; Genetic Transcription; Human; IL8 gene; ISG15 gene; Immune response; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Interferons; Interleukin-6; Lead; Ligase; Lung; Mediating; Modification; Molecular; NF-kappa B; NF1 gene; Nuclear; Pathogenesis; Pathologic; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Post-Translational Protein Processing; Process; Property; Proteins; Regulation; Reporting; Rest; Role; Scheme; Sepsis; Serine; Severities; Site; Stimulus; Structure of parenchyma of lung; Transcriptional Activation; Transgenic Mice; Ubiquitin Like Proteins; Up-Regulation; attenuation; chemokine; endothelial dysfunction; isopeptidase; lung injury; lung microvascular endothelial cells; mouse model; neutrophil; novel therapeutics; overexpression; p65; response; side effect; small molecule; small molecule inhibitor; transcription factor; ubiquitin-protein ligase

Abstract Excessive lung microvascular endothelial inflammation is a pathological hallmark of acute respiratory distress syndrome (ARDS). Upon inflammatory stimuli, lung endothelial cells (ECs) increase chemokine and adhesion molecule expression, such as IL-6, and intercellular adhesion molecule 1, ultimately causing neutrophil accumulation at the site of inflammation, endothelial barrier dysfunction, and lung tissue damage in acute lung injury and sepsis. Nuclear transcriptional factor κB (NF-κB) plays a pivotal role in EC inflammation. Inflammatory stimuli trigger phosphorylation of NF-κB component p65, leading to increase p65 transcriptional activity. We revealed that NF-κBp65 can be ISGylated. The ISGylated p65 is inactive in the resting ECs. We also discovered that SCFFBXL19 E3 ligase catalyzes ISGylation of p65, impedes p65 phosphorylation, and mitigates lung EC inflammation. These observations led us to hypothesize that p65 ISGylation by SCFFBXL19 dampens its phosphorylation, transcriptional activation, and lung EC inflammation; and increases in FBXL19 stability mitigates lung EC inflammation through reducing NF-kB activation. To better understand the new modification of p65, in this proposal, we will determine molecular mechanisms by which SCFFBXL19 catalyzes p65 ISGylation and its role in human lung microvascular EC inflammation. And then, we will determine the molecular mechanisms by which p65 ISGylation impedes its phosphorylation and activation in human lung microvascular ECs. Lastly, we will determine if stabilization of FBXL19 alleviates lung EC inflammation in murine models of acute lung injury and sepsis. This application will be the first to characterize SCFFBXL19-mediated ISGylation of NF-κBp65 and determine its role in the regulation of p65 phosphorylation, transcriptional activation, and lung EC inflammation in acute lung injury and sepsis.

摘要 过度的肺微血管内皮炎症是急性肺损伤的病理标志。 呼吸窘迫综合征（ARDS）。在炎症刺激下，肺内皮细胞（EC） 增加趋化因子和粘附分子表达，如IL-6和细胞间粘附 分子1，最终导致中性粒细胞聚集在炎症部位，内皮 屏障功能障碍和急性肺损伤和脓毒症中的肺组织损伤。核 转录因子κB（NF-κB）在EC炎症中发挥关键作用。炎性刺激 触发NF-κB组分p65的磷酸化，导致p65转录活性增加。 我们发现NF-κ Bp 65可以被ISG化。ISG化的p65在静息EC中是无活性的。 我们还发现，SCFFBXL 19 E3连接酶催化p65的ISG化，阻碍p65 磷酸化，并减轻肺EC炎症。这些观察使我们假设 SCFFBXL 19对p65 ISG的修饰抑制了其磷酸化、转录激活和肺 EC炎症;并且FBXL 19稳定性的增加通过以下途径减轻肺EC炎症： 降低NF-κ B活化。为了更好地理解p65的新修改，在本提案中，我们 将确定SCFFBXL 19催化p65 ISGylation的分子机制及其在 人肺微血管EC炎症。然后，我们将确定分子 人肺组织中p65 ISG化阻碍其磷酸化和活化的机制 微血管内皮细胞。最后，我们将确定FBXL 19的稳定性是否会增加肺EC 急性肺损伤和脓毒症小鼠模型中的炎症。该应用程序将是第一个 表征SCFFBXL 19介导的NF-κ Bp 65 ISG化，并确定其在调节中的作用 急性肺损伤中p65磷酸化、转录激活和肺EC炎症的关系 和败血症