Yamane Daisuke, Zahoor Muhammad A, Mohamed Yassir M, Azab Walid, Kato Kentaro, Tohya Yukinobu, Akashi Hiroomi
Department of Veterinary Microbiology, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
Department of Veterinary Microbiology, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
J Biol Chem. 2009 May 15;284(20):13648-13659. doi: 10.1074/jbc.M807498200. Epub 2009 Mar 17.
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.
1-磷酸鞘氨醇（S1P）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S1P来促进这些功能。我们在此报告，丙型肝炎病毒（HCV）的近亲牛病毒性腹泻病毒（BVDV）的非结构蛋白NS3与其丝氨酸蛋白酶活性无关，可结合并抑制SphK1的催化活性，而HCV NS3不影响SphK1活性。还发现未切割的BVDV NS2-3与SphK1相互作用并抑制SphK1。我们怀疑BVDV NS3和NS2-3对SphK1活性的抑制可能有利于病毒复制，因为通过小干扰RNA、化学抑制剂抑制SphK1或催化无活性的SphK1过表达会导致病毒复制增强，尽管SphK1抑制导致病毒复制增强的机制尚不清楚。由于SphK1的过表达显著减弱了感染致细胞病变性BVDV的细胞中凋亡的诱导，因此也提示了SphK1抑制在病毒细胞病变发生中的作用。这些发现表明，这种病毒靶向SphK以调节其催化活性。
