ISGylation regulates lung endothelial inflammation

ISGylation 调节肺内皮炎症

• 批准号: 10180376
• 负责人: Yutong Zhao
• 金额: $ 58.82万
• 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/10180376
• 关键词: Acute Lung Injury; Adult 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; 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.

抽象的 过度肺微血管内皮炎症是急性的病理标志 呼吸窘迫综合征（ARDS）。在炎症性刺激下，肺内皮细胞（EC） 增加趋化因子和粘附分子表达，例如IL-6和细胞间粘合剂 分子1，最终导致炎症部位的中性粒细胞积累 急性肺损伤和败血症中的屏障功能障碍和肺组织损伤。核 转录因子κB（NF-κB）在EC炎症中起关键作用。炎症性刺激 触发NF-κB成分p65的磷酸化，导致p65转录活性增加。 我们揭示了NF-κBP65可以被静置。静态EC中的iSgymet P65在静止的EC中是不活跃的。 我们还发现SCFFBXL19 E3连接酶催化p65，阻碍p65 磷酸化并减轻肺EC炎症。这些观察结果使我们假设 SCFFBXL19的p65 iSgyLation抑制了其磷酸化，转录激活和肺 EC炎症； FBXL19稳定性的增加可通过 减少NF-KB激活。为了更好地了解p65的新修改，在此提案中，我们 将确定SCFFFBXL19催化p65 iSgyLation及其在其中的作用的分子机制 人肺微血管EC炎症。然后，我们将确定分子 p65 Isgylation阻碍其磷酸化和激活在人肺中的机制 微血管EC。最后，我们将确定FBXL19的稳定是否减轻了肺EC 急性肺损伤和败血症的鼠模型中的炎症。此应用程序将是第一个 表征NF-κBP65的SCFFFBXL19介导的Isgylation，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 和败血症。