UCHL1 Regulates Radiation Lung Injury via Sphingosine Kinase-1.
UCHL1 Regulates Radiation Lung Injury via Sphingosine Kinase-1.
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GADD45a 是我们之前报道的一种基因，它是急性肺损伤反应的调节因子。由于去泛素化酶 UCHL1（泛素 C 末端水解酶 L1）的表达减少，GADD45a−/− 小鼠的 Akt 表达减少，Akt 泛素化增加，而 GADD45a−/− 小鼠对辐射引起的肺损伤 (RILI) 的易感性增加。另外，我们报道了鞘脂在 RILI 中的作用，SphK1−/−（鞘氨醇激酶 1）小鼠的 RILI 敏感性增加证明了这一点。已知的 SphK1 多泛素化表明 UCHL1 和 RILI 中的鞘脂信号传导之间存在机制联系。因此，我们假设UCHL1对SphK1泛素化的调节介导了RILI。最初，接受辐射的人肺内皮细胞 (EC) 表现出 UCHL1 和 SphK1 的显着上调。通过 SphK1 的免疫沉淀和泛素的蛋白质印迹证实了放射后 EC SphK1 的泛素化。此外，在放射之前，用针对 UCHL1 的 siRNA 转染的 EC 或用 LDN-5744（作为 UCHL1 抑制剂）预处理的 EC 在两种情况下都减少了泛素化的 SphK1。此外，通过跨内皮电阻测量 UCHL1 的抑制减弱了鞘脂介导的 EC 屏障增强。最后，LDN 预处理显着增加了小鼠 RILI 的严重程度。我们的数据支持辐射后 SphK1 表达的调节是由 UCHL1 介导的事实。调节 UCHL1 影响鞘脂信号传导可能代表一种新的 RILI 治疗策略。
GADD45a is a gene we previously reported as a mediator of responses to acute lung injury. GADD45a−/− mice express decreased Akt and increased Akt ubiquitination due to the reduced expression of UCHL1 (ubiquitin c-terminal hydrolase L1), a deubiquitinating enzyme, while GADD45a−/− mice have increased their susceptibility to radiation-induced lung injury (RILI). Separately, we have reported a role for sphingolipids in RILI, evidenced by the increased RILI susceptibility of SphK1−/− (sphingosine kinase 1) mice. A mechanistic link between UCHL1 and sphingolipid signaling in RILI is suggested by the known polyubiquitination of SphK1. Thus, we hypothesized that the regulation of SphK1 ubiquitination by UCHL1 mediates RILI. Initially, human lung endothelial cells (EC) subjected to radiation demonstrated a significant upregulation of UCHL1 and SphK1. The ubiquitination of EC SphK1 after radiation was confirmed via the immunoprecipitation of SphK1 and Western blotting for ubiquitin. Further, EC transfected with siRNA specifically for UCHL1 or pretreated with LDN-5744, as a UCHL1 inhibitor, prior to radiation were noted to have decreased ubiquitinated SphK1 in both conditions. Further, the inhibition of UCHL1 attenuated sphingolipid-mediated EC barrier enhancement was measured by transendothelial electrical resistance. Finally, LDN pretreatment significantly augmented murine RILI severity. Our data support the fact that the regulation of SphK1 expression after radiation is mediated by UCHL1. The modulation of UCHL1 affecting sphingolipid signaling may represent a novel RILI therapeutic strategy.
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影响因子：
3.9
作者：
Jin C;Yu W;Lou X;Zhou F;Han X;Zhao N;Lin B
通讯作者：
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DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
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DOI：
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发表时间：
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期刊：
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影响因子：
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影响因子：
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作者：
通讯作者：
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DOI：
10.1016/s0360-3016(00)00482-x
发表时间：
2000-07-01
影响因子：
7
作者：
Rübe, CE;Uthe, D;Rübe, C
通讯作者：
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