Sphingosine kinase mediates activation of extracellular signal-related kinase and Akt by respiratory syncytial virus
Sphingosine kinase mediates activation of extracellular signal-related kinase and Akt by respiratory syncytial virus
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DOI：
10.1165/rcmb.2003-0424oc
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发表时间：
2004-06-01
影响因子：
6.4
通讯作者：
Hunninghake, GW
中科院分区：
文献类型：
--
作者：
Monick, MM;Cameron, K;Hunninghake, GW
呼吸道合胞病毒(RSV)优先感染肺上皮细胞。被感染的细胞在感染后仍能存活。这种延长的存活是由于RSV诱导的促生存通路的激活，包括Akt和细胞外信号相关激酶(ERK)。鞘氨醇I-磷酸(SIP)是一种鞘糖脂代谢物，与细胞生存有关。它是由神经酰胺酶(神经鞘氨醇的生成)和鞘氨醇激酶(神经鞘氨醇的生成)的顺序激活产生的。在这些研究中，我们发现RSV刺激了肺上皮细胞中中性神经酰胺酶和鞘氨醇激酶的活性。这两种酶的激活联合作用可降低促凋亡神经酰胺，增加抗凋亡的S1P。S1P在几分钟内激活Akt和ERK，抑制鞘氨醇激酶阻断RSV诱导的ERK和Akt的激活，导致病毒感染后细胞加速死亡。RSV感染最终确实会杀死受感染的细胞，但细胞生存途径的激活会显着推迟细胞的死亡。这项研究是首次在病毒感染的背景下将鞘脂代谢物与细胞生存机制联系起来的证据。
Respiratory syncytial virus (RSV) preferentially infects lung epithelial cells. Infected cells remain viable well into the infection. This prolonged survival results from RSV-induced activation of pro-survival pathways, including Akt and extracellular signal-related kinase (ERK). Sphingosine I-phosphate (SIP) is a sphingolipid metabolite with demonstrated links to cell survival. It is enzymatically generated by sequential activation of ceramidase (generation of sphingosine) and sphingosine kinase (generation of SIP). In these studies, we found that RSV stimulated neutral ceramidase and sphingosine kinase activities in lung epithelial cells. The combined effect of activation of these two enzymes would decrease proapoptotic ceramide and increase antiapoptotic S1P. S1P activated Akt and ERK within minutes, and inhibition of sphingosine kinase blocked RSV-induced ERK and Akt activation, leading to accelerated cell death after viral infection. RSV infection does eventually kill infected cells but activation of cell survival pathways significantly delays cell death. The studies are the first evidence linking sphingolipid metabolites to cell survival mechanisms in the context of a viral infection.