Deubiquitinating and inhibiting Hsp90 by USP40 mitigates lung injury

USP40 去泛素化和抑制 Hsp90 可减轻肺损伤

• 批准号: 10618145
• 负责人: JING ZHAO
• 金额: $ 44.37万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618145
• 关键词: Acetylation; Acute; Acute Lung Injury; Alveolar; Animal Model; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Blood capillaries; Cells; Data; Deubiquitinating Enzyme; Deubiquitination; Development; Docking; Edema; Endothelial Cells; Endothelium; Endotoxins; Enzymes; Exhibits; Extravasation; Foundations; Generations; HSP 90 inhibition; Heat-Shock Proteins 90; Hospitals; Inflammatory; Inflammatory Response; Knockout Mice; Lead; Life; Lipopolysaccharides; Lung; Lysine; Mediating; Molecular; Monoubiquitination; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Permeability; Phase; Phosphorylation; Play; Pneumonia; Post-Translational Protein Processing; Process; Proteins; Regulation; Role; Scheme; Sepsis; Severities; Site; Stress; Superbug; Therapeutic; Ubiquitin; Ubiquitination; attenuation; cell type; cytokine release syndrome; endothelial dysfunction; inhibitor; lung injury; lung preservation; mortality; mouse model; neutrophil; novel therapeutic intervention; novel therapeutics; preservation; protein folding; protein protein interaction; response; restraint; side effect; small molecule inhibitor; therapeutic target; ubiquitin isopeptidase

Abstract Acute lung injury (ALI) is a life-threatening inflammatory lung condition that is most commonly caused by pneumonia or sepsis. ALI-related mortality remains at unexpectedly high levels. Hence, a new therapeutic strategy for ALI is needed. Uncontrolled cytokine storm, neutrophil influx into alveolar spaces, and leakage from capillaries are the hallmarks of ALI, thus, a promising therapeutic strategy in the acute phase of ALI is to restrain pro-inflammatory responses and capillary barrier disruption simultaneously. Heat shock protein 90 (Hsp90) has been known to contribute to the pathogenesis of ALI by promoting pro-inflammatory responses in a variety of lung cell types and increasing endothelial cell (EC) permeability. Inhibition of Hsp90 activity by small molecule inhibitors have been shown to reduce the severity of ALI in animal models dramatically; however, molecular regulation of Hsp90 has not been well studied. We discovered that Hsp90 can be mono-ubiquitinated and the mono-ubiquitination may compete with acetylation of Hsp90 to increase Hsp90 activity. We identified that USP40, a DUB, deubiquitinates Hsp90, thus resulting in inhibiting Hsp90. We hypothesize that deubiquitinating and inhibiting Hsp90 by USP40 mitigate lung injury by suppressing pro-inflammatory responses and preserving EC barrier integrity. We will determine the molecular mechanisms by which USP40 deubiquitinates and inactivates Hsp90. Then, we will focus on determining the molecular mechanisms by which USP40 mitigates pro-inflammatory responses and pulmonary EC barrier disruption through deubiquitination of Hsp90. Lastly, we will determine if USP40 de-mono-ubiquitination of Hsp90 plays a protective role in murine models of ALI. These studies will be the first to elucidate the protective role of inactivating Hsp90 by USP40 against lung injury.

摘要 急性肺损伤（ALI）是一种危及生命的炎症性肺部疾病， 是由肺炎或败血症引起的与ALI相关的死亡率仍然处于出乎意料的高水平。因此，我们认为， 需要一种新的治疗ALI的策略。不受控制的细胞因子风暴，中性粒细胞流入 肺泡腔和毛细血管渗漏是ALI的标志，因此， 急性期ALI的治疗策略是抑制促炎反应， 同时破坏毛细血管屏障。已知热休克蛋白90（Hsp90） 通过促进各种炎症反应，促进ALI的发病机制。 肺细胞类型和增加内皮细胞（EC）渗透性。Hsp90活性的抑制 在动物模型中，小分子抑制剂已显示出降低ALI的严重性 然而，Hsp90的分子调控尚未得到很好的研究。我们发现 Hsp90可以被单泛素化，并且单泛素化可能与乙酰化竞争 增加Hsp90的活性。我们发现USP 40（一种DUB）可以去遍在化Hsp90， 从而导致抑制Hsp90。我们假设，通过去泛素化和抑制Hsp90， USP 40通过抑制促炎反应和保护EC屏障减轻肺损伤 完整我们将确定USP40去泛素化的分子机制， 使Hsp90失活。然后，我们将集中精力确定分子机制， USP 40通过以下方式减轻促炎反应和肺EC屏障破坏 热休克蛋白90的去泛素化。最后，我们将确定USP40是否能使Hsp90去单泛素化 在ALI小鼠模型中起保护作用。这些研究将首次阐明 USP 40灭活Hsp90对肺损伤的保护作用。

项目成果

Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival.

• DOI: 10.1161/circresaha.121.319100
• 发表时间: 2022-03-04
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Kudryashova TV;Dabral S;Nayakanti S;Ray A;Goncharov DA;Avolio T;Shen Y;Rode A;Pena A;Jiang L;Lin D;Baust J;Bachman TN;Graumann J;Ruppert C;Guenther A;Schmoranzer M;Grobs Y;Eve Lemay S;Tremblay E;Breuils-Bonnet S;Boucherat O;Mora AL;DeLisser H;Zhao J;Zhao Y;Bonnet S;Seeger W;Pullamsetti SS;Goncharova EA
• 通讯作者: Goncharova EA

Non-Lethal Doses of RSL3 Impair Microvascular Endothelial Barrier through Degradation of Sphingosie-1-Phosphate Receptor 1 and Cytoskeletal Arrangement in A Ferroptosis-Independent Manner.

• DOI: 10.3390/biomedicines11092451
• 发表时间: 2023-09-04
• 期刊: Biomedicines
• 影响因子: 4.7