Sphingosine kinase-2 maintains viral latency and survival for KSHV-infected endothelial cells.
Sphingosine kinase-2 maintains viral latency and survival for KSHV-infected endothelial cells.
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鞘氨醇激酶 2 维持 KSHV 感染内皮细胞的病毒潜伏期和存活率
DOI：
10.1371/journal.pone.0102314
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Parsons C
中科院分区：
文献类型：
--
作者：
Dai L;Plaisance-Bonstaff K;Voelkel-Johnson C;Smith CD;Ogretmen B;Qin Z;Parsons C
鞘氨醇激酶（SphK1 和 SphK2）对鞘氨醇进行磷酸化，生成 1-磷酸鞘氨醇 (S1P)，这是一种生物活性鞘脂，可促进体内癌细胞存活和肿瘤进展。我们最近报道，靶向 SphK2 会诱导被卡波西肉瘤相关疱疹病毒 (KSHV) 感染的人原发性渗出性淋巴瘤 (PEL) 细胞系凋亡，这部分是通过抑制典型 NF-κB 激活而发生的。相比之下，SphK2 的药物抑制对未感染的 B 细胞系或来自健康供体的循环人类 B 细胞的影响很小。因此，我们设计了其他研究，利用原代人内皮细胞来探索在 SphK2 靶向期间观察到的 KSHV 感染细胞选择性死亡的机制。使用 RNA 干扰和临床相关的药理学方法，我们发现靶向 SphK2 通过诱导病毒裂解基因表达选择性诱导 KSHV 感染的内皮细胞凋亡。此外，这种效应是通过抑制调节病毒潜伏期和信号转导的 KSHV-microRNA 来实现的，其中包括靶向 IκBα 以促进 NF-κB 激活的 miR-K12-1，而 miR-K12-1 的异位表达可在 SphK2 抑制期间恢复 KSHV 感染的内皮细胞的 NF-κB 激活和活力。这些数据阐明了 KSHV 感染的内皮细胞的一种新的生存机制和潜在的治疗靶点：SphK2 相关的病毒潜伏期维持。
Phosphorylation of sphingosine by sphingosine kinases (SphK1 and SphK2) generates sphingosine-1-phosphate (S1P), a bioactive sphingolipid which promotes cancer cell survival and tumor progression in vivo. We have recently reported that targeting SphK2 induces apoptosis for human primary effusion lymphoma (PEL) cell lines infected by the Kaposi’s sarcoma-associated herpesvirus (KSHV), and this occurs in part through inhibition of canonical NF-κB activation. In contrast, pharmacologic inhibition of SphK2 has minimal impact for uninfected B-cell lines or circulating human B cells from healthy donors. Therefore, we designed additional studies employing primary human endothelial cells to explore mechanisms responsible for the selective death observed for KSHV-infected cells during SphK2 targeting. Using RNA interference and a clinically relevant pharmacologic approach, we have found that targeting SphK2 induces apoptosis selectively for KSHV-infected endothelial cells through induction of viral lytic gene expression. Moreover, this effect occurs through repression of KSHV-microRNAs regulating viral latency and signal transduction, including miR-K12-1 which targets IκBα to facilitate activation of NF-κB, and ectopic expression of miR-K12-1 restores NF-κB activation and viability for KSHV-infected endothelial cells during SphK2 inhibition. These data illuminate a novel survival mechanism and potential therapeutic target for KSHV-infected endothelial cells: SphK2-associated maintenance of viral latency.