The specific SM molecular species that these endogenous SM species interacted with HCV nonstructural 5B polymerase to enhance viral replication

这些内源性 SM 种类与 HCV 非结构 5B 聚合酶相互作用以增强病毒复制的特定 SM 分子种类

• 批准号: 21390145
• 负责人: KOHARA Michinori
• 金额: $ 11.81万
• 依托单位: 財団法人東京都医学総合研究所 (2011)Tokyo Metropolitan Organization for Medical Research (2009-2010)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390145/
• 关键词: 細胞; スフィンゴ脂質; HCV複製; 脂質ラフト; RdRp; C型肝炎ウイルス; SPT; 細胞内逆輸送; 遺伝子複製; スフィンゴ肪質

Lipids are key components in the viral life cycle that affect host-pathogen interactions. In this study, we investigated the effect of HCV infection on sphingolipid metabolism, especially on endogenous SM levels, and the relationship between HCV replication and endogenous SM molecular species. We demonstrated that HCV induces the expression of the genes encoding sphingomyelin(SM) synthases. We observed associated increases of both total and individual sphingolipid molecular species, as assessed in human hepatocytes and in the detergent-resistant membrane(DRM) fraction in which HCV replicates. SGMS-1 expression had a strong correlation with HCV replication. Inhibition of sphingolipid biosynthesis with a hepatotropic serine palmitoyltransferase inhibitor, NA808, suppressed HCV-RNA production while also interfering with sphingolipid metabolism. Further, we identified the specific SM molecular species that comprise the DRM fraction and demonstrated that these endogenous SM species interacted with HCV nonstructural 5B polymerase to enhance viral replication. Our results reveal that HCV alters sphingolipid metabolism to promote viral replication, providing new insights into the formation of the HCV replication complex and the involvement of host lipids in the HCV life cycle.

脂质是病毒生命周期中影响宿主-病原体相互作用的关键成分。在本研究中，我们研究了HCV感染对鞘脂代谢的影响，特别是对内源性SM水平的影响，以及HCV复制与内源性SM分子种类的关系。我们证明HCV诱导鞘磷脂（SM）合成酶编码基因的表达。我们观察到，在人肝细胞和HCV复制的耐洗涤剂膜（DRM）部分中，总鞘脂分子种类和个体鞘脂分子种类都有相关的增加。SGMS-1表达与HCV复制有很强的相关性。嗜肝丝氨酸棕榈酰基转移酶抑制剂NA808抑制鞘脂生物合成，抑制HCV-RNA的产生，同时也干扰鞘脂代谢。此外，我们确定了包含DRM部分的特定SM分子种类，并证明这些内源性SM物种与HCV非结构5B聚合酶相互作用以增强病毒复制。我们的研究结果表明，HCV改变鞘脂代谢以促进病毒复制，为HCV复制复合物的形成和宿主脂质在HCV生命周期中的参与提供了新的见解。

项目成果

An orally available, small-molecule interferon inhibits hepatitis C virus replication

口服小分子干扰素可抑制丙型肝炎病毒复制

• 发表时间: 2012
• 期刊: Sci. Comm
• 作者: Konoishi H.;Okamoto K.;Ohmori Y.;Yoshino H.;Ohmori H.;Ashiara M.;Hirata Y.;Ohta A.;Sakamoto H.;Hada N.;Katsume A.;Kohara M.;MOrikawa K.;Tsukuda T.;Shimma N.;Foster G.;Alazawi W.;Aoki Y.;Arisawa M.;Sudoh M.
• 通讯作者: Sudoh M.

Monoclonal antibody 2-152a suppresses hepatitis C virus infection thorough betaine/GABA transporter-1

单克隆抗体2-152a通过甜菜碱/GABA转运蛋白1抑制丙型肝炎病毒感染

• 发表时间: 2011
• 期刊: J. Infectious Disease
• 作者: Satoh M.;Saito M.;Takano T.;Kasama Y.;Nishimura T.;Nishito Y.;Hirata Y.;Arai M.;Sudoh M.;Kai C.;Kohara M.;Tsukiyama-Kohara K.
• 通讯作者: Tsukiyama-Kohara K.

Interferon-lambda plays a critical role in antiviral response in human hepatocytes

干扰素-lambda 在人肝细胞的抗病毒反应中发挥着关键作用

• 发表时间: 2011
• 作者: *Ebisuno;Y.;* Katagiri;K.;Katakai;T.;Ueda;Y.;Nemoto;T.;Inada;H.;Nabekura;J.;Okada;T.;Kannagi;R.;Tanaka;T.;Miyasaka;M.;Hogg;N. & Kinashi;T;石戸聡;Hirata Y.
• 通讯作者: Hirata Y.

Suppression of sphingomyelin augmented by hepatitis C virus has robust anti-viral effects in human livers

丙型肝炎病毒增强的鞘磷脂抑制对人类肝脏具有强大的抗病毒作用

• 发表时间: 2011
• 作者: Ohno;H.;Hirata Y.
• 通讯作者: Hirata Y.

Novel infectious clone of HCV 1a strain HCV-RMT efficiently replicate in vitro and in vivo using adaptive mutations

HCV 1a 株 HCV-RMT 的新型感染性克隆利用适应性突变在体外和体内有效复制

• 发表时间: 2011
• 作者: Bai;Z.;* Hayasaka;H.;Kobayashi;M.;Li;W.;Guo;Z.;Jang;M. H.;Kondo;A.;Choi;B.;Iwakura;Y. & Miyasaka;M;Tokunaga Y.
• 通讯作者: Tokunaga Y.