Inhibition of Sphingosine Kinase by Bovine Viral Diarrhea Virus NS3 Is Crucial for Efficient Viral Replication and Cytopathogenesis*
Inhibition of Sphingosine Kinase by Bovine Viral Diarrhea Virus NS3 Is Crucial for Efficient Viral Replication and Cytopathogenesis*
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DOI：
10.1074/jbc.m807498200
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发表时间：
2009-05
影响因子：
4.8
通讯作者：
D. Yamane;M. Zahoor;Y. M. Mohamed;W. Azab;Kentaro Kato;Y. Tohya;H. Akashi
中科院分区：
文献类型：
--
作者：
D. Yamane;M. Zahoor;Y. M. Mohamed;W. Azab;Kentaro Kato;Y. Tohya;H. Akashi
1-磷酸鞘氨醇（S1 P）是一种生物活性鞘脂，参与多种细胞功能，包括存活、增殖、肿瘤发生、炎症和免疫。鞘氨醇激酶（SphK）通过将鞘氨醇转化为S1 P而有助于这些功能。我们在这里报告的非结构蛋白NS 3从牛病毒性腹泻病毒（BVDV），丙型肝炎病毒（HCV）的近亲，结合并抑制SphK 1的催化活性独立于其丝氨酸蛋白酶活性，而HCV NS 3不影响SphK 1的活性。还发现来自BVDV的未裂解的NS 2 -3与SphK 1相互作用并抑制SphK 1。我们怀疑BVDV NS 3和NS 2 -3对SphK 1活性的抑制可能有利于病毒复制，因为小干扰RNA、化学抑制剂或无催化活性SphK 1的过表达对SphK 1的抑制导致病毒复制增强，尽管SphK 1抑制导致病毒复制增强的机制尚不清楚。由于SphK 1过表达显著减弱了致细胞病变BVDV感染细胞中的细胞凋亡诱导，因此也表明SphK 1抑制在病毒致细胞病变中的作用。这些发现表明SphK被这种病毒靶向以调节其催化活性。
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid implicated in diverse cellular functions including survival, proliferation, tumorigenesis, inflammation, and immunity. Sphingosine kinase (SphK) contributes to these functions by converting sphingosine to S1P. We report here that the nonstructural protein NS3 from bovine viral diarrhea virus (BVDV), a close relative of hepatitis C virus (HCV), binds to and inhibits the catalytic activity of SphK1 independently of its serine protease activity, whereas HCV NS3 does not affect SphK1 activity. Uncleaved NS2-3 from BVDV was also found to interact with and inhibit SphK1. We suspect that inhibition of SphK1 activity by BVDV NS3 and NS2-3 may benefit viral replication, because SphK1 inhibition by small interfering RNA, chemical inhibitor, or overexpression of catalytically inactive SphK1 results in enhanced viral replication, although the mechanisms by which SphK1 inhibition leads to enhanced viral replication remain unknown. A role of SphK1 inhibition in viral cytopathogenesis is also suggested as overexpression of SphK1 significantly attenuates the induction of apoptosis in cells infected with cytopathogenic BVDV. These findings suggest that SphK is targeted by this virus to regulate its catalytic activity.