Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury.
Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury.
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溶血磷脂酸受体 1 的不稳定可减少细胞因子的释放并预防肺损伤。
DOI：
10.1016/j.ebiom.2016.07.020
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发表时间：
2016-08
期刊：
影响因子：
11.1
通讯作者：
Zhao, Yutong
中科院分区：
文献类型：
--
作者：
Zhao, Jing;Wei, Jianxin;Dong, Su;Bowser, Rachel K.;Zhang, Lina;Jacko, Anastasia M.;Zhao, Yutong
溶血磷脂酸受体1（LPA 1）是治疗肺部炎症性疾病的药物靶点。然而，LPA1稳定性的分子调控，一个关键影响其生物活性的因素，在很大程度上仍然未知。在这里，我们确定了两种酶，调节LPA1泛素化和去泛素化的平衡。泛素E3连接酶Nedd4L靶向LPA 1，用于其在溶酶体中的位点特异性泛素化和降解。Nedd4L负调节LPA-LPA1介导的细胞因子释放。LPA1的稳定性被泛素特异性蛋白酶11（USP 11）上调，其使LPA1去泛素化并增强LPA1介导的促炎作用。LPA 1在静止细胞中与USP11相关，而LPA处理触发LPA 1与USP11解离，进而与Nedd4L结合。USP11的敲低或抑制降低了LPA1稳定性、LPA1水平和LPA1-CD14相互作用复合物;从而减少了临床前小鼠模型中LPA和LPS诱导的炎症反应和肺损伤。因此，我们的研究结果确定了泛素E3连接酶和去泛素化酶负责调节LPA 1的稳定性和生物活性。这项研究为开发抗炎分子以减轻肺损伤提供了潜在的靶点。Nedd4L泛素化LPA1并减少LPA1信号传导。USP11去泛素化并稳定LPA1，从而促进LPA1和LPS介导的促炎反应。抑制USP11可减少LPS诱导的急性肺损伤。溶血磷脂酸（LPA）及其受体（LPA1）通过触发细胞因子释放和中性粒细胞流入肺部，在肺部炎症中发挥关键作用。在这里，我们表明，LPA1是泛素化和降解的溶酶体，这一过程是由泛素E3连接酶Nedd4L介导的。此外，我们揭示了去泛素化酶USP 11通过靶向和去泛素化LPA 1来稳定LPA 1。为了研究LPA 1的不稳定是否减少肺损伤，在内毒素攻击之前抑制或下调USP 11。LPA1的失稳减少了临床前肺损伤小鼠模型中细胞因子的释放和肺部炎症。
Lysophosphatidic acid receptor 1 (LPA1) is a druggable target for treating pulmonary inflammatory diseases. However, the molecular regulation of LPA1 stability, a factor that critically impacts its biological activity, remains largely unknown. Here we identify two enzymes that regulate the balance of LPA1 ubiquitination and deubiquitination. Ubiquitin E3 ligase Nedd4L targets LPA1 for its site specific ubiquitination and degradation in the lysosome. Nedd4L negatively regulates LPA-LPA1-mediated cytokine release. The stability of LPA1 is up-regulated by ubiquitin-specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1-mediated pro-inflammatory effects. LPA1 is associated with USP11 in quiescent cells, while LPA treatment triggers LPA1 dis-association with USP11 and in turn binding to Nedd4L. Knockdown or inhibition of USP11 reduces LPA1 stability, levels of LPA1, and LPA1-CD14 interaction complex; thereby diminishing both LPA- and LPS-induced inflammatory responses and lung injury in preclinical murine models. Thus, our findings identify an ubiquitin E3 ligase and a deubiquitinating enzyme responsible for regulation of LPA1 stability and biological activities. This study provides potential targets for the development of anti-inflammatory molecules to lessen lung injury. Nedd4L ubiquitinates LPA1 and diminishes LPA1 signaling. USP11 deubiquitinates and stabilizes LPA1, thus promotes LPA1- and LPS-mediated pro-inflammatory response. Inhibition of USP11 reduces LPS-induced acute lung injury. Lysophosphatidic acid (LPA) and its receptor (LPA1) play a critical role in lung inflammation through triggering cytokine release and neutrophil influx to the lungs. Here, we show that LPA1 is ubiquitinated and degraded in the lysosome, and the process is mediated by the ubiquitin E3 ligase Nedd4L. Further, we reveal that a deubiquitination enzyme USP11 stabilizes LPA1 by targeting and deubiquitinating LPA1. To investigate whether destabilization of LPA1 diminishes lung injury, USP11 was inhibited or down-regulated prior to endotoxin challenge. Destabilization of LPA1 reduces cytokine release and lung inflammation in a preclinical murine model of lung injury.
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影响因子：
4
作者：
Rotin D;Staub O
通讯作者：
Staub O
影响因子：
16.6
作者：
Boase, Natasha A.;Rychkov, Grigori Y.;Townley, Scott L.;Dinudom, Anuwat;Candi, Eleanora;Voss, Anne K.;Tsoutsman, Tatiana;Semsarian, Chris;Melino, Gerry;Koentgen, Frank;Cook, David I.;Kumar, Sharad
通讯作者：
Kumar, Sharad
影响因子：
12.8
作者：
Park, Beom Seok;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh
影响因子：
4.8
作者：
Kamynina, E;Debonneville, C;Staub, O
通讯作者：
Staub, O
在硬皮病小鼠模型中通过基因缺失或溶血磷脂酸受体 1 的药理学拮抗作用改善真皮纤维化。
影响因子：
--
作者：
Castelino, Flavia V.;Seiders, Jon;Bain, Gretchen;Brooks, Sarah F.;King, Christopher D.;Swaney, James S.;Lorrain, Daniel S.;Chun, Jerold;Luster, Andrew D.;Tager, Andrew M.
通讯作者：
Tager, Andrew M.