Hepatitis C virus core protein abrogates the DDX3 function that enhances IPS-1-mediated IFN-beta induction.
Hepatitis C virus core protein abrogates the DDX3 function that enhances IPS-1-mediated IFN-beta induction.
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DOI：
10.1371/journal.pone.0014258
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发表时间：
2010-12-08
期刊：
影响因子：
3.7
通讯作者：
Seya T
中科院分区：
文献类型：
--
作者：
Oshiumi H;Ikeda M;Matsumoto M;Watanabe A;Takeuchi O;Akira S;Kato N;Shimotohno K;Seya T
DEAD盒解旋酶DDX 3在非感染的人类细胞中组装IPS-1（也称为Cardif、MAVS或VISA），其中表达最少量的RIG-I样受体（RLR）蛋白。DDX 3 C-末端区域直接结合IPS-1 CARD样结构域以及N-末端丙型肝炎病毒（HCV）核心蛋白。DDX 3物理结合病毒RNA以形成含有IPS-1的斑点，其通过共聚焦显微镜可见。HCV polyU/UC诱导IPS-1介导的干扰素（IFN）-β启动子激活，这是由共转染DDX 3增强。DDX 3斑点位于产生HCV颗粒的脂滴（LD）附近。在这里，我们报告，HCV核心蛋白干扰DDX 3增强IPS-1信号在HEK 293细胞和肝细胞Oc细胞。与DEAD盒解旋酶RIG-I和MDA 5不同，DDX 3组成型表达并与IPS-1共定位在线粒体周围。然而，在具有HCV复制子的肝细胞（O细胞）中，即使当DDX 3共表达时，DDX 3/IPS-1增强的IFN-β诱导也在很大程度上被消除。DDX 3斑点几乎不与IPS-1融合，并且在O细胞中部分组装在位于LD附近的HCV核心蛋白中，尽管在一些O细胞中IPS-1减少或散布在线粒体之外。DDX 3在复制子阴性或无核心复制子阳性细胞中的表达未能引起复合物形成或LD关联。HCV核心蛋白和DDX 3仅部分共定位于复制子表达细胞中。由于已报道HCV核心蛋白通过与DDX 3结合来促进HCV复制，因此核心蛋白似乎将DDX 3从IFN诱导模式转换为HCV复制模式。这些结果使我们能够得出结论，HCV感染是通过调节DDX 3的双重功能来促进的。
The DEAD box helicase DDX3 assembles IPS-1 (also called Cardif, MAVS, or VISA) in non-infected human cells where minimal amounts of the RIG-I-like receptor (RLR) protein are expressed. DDX3 C-terminal regions directly bind the IPS-1 CARD-like domain as well as the N-terminal hepatitis C virus (HCV) core protein. DDX3 physically binds viral RNA to form IPS-1-containing spots, that are visible by confocal microscopy. HCV polyU/UC induced IPS-1-mediated interferon (IFN)-beta promoter activation, which was augmented by co-transfected DDX3. DDX3 spots localized near the lipid droplets (LDs) where HCV particles were generated. Here, we report that HCV core protein interferes with DDX3-enhanced IPS-1 signaling in HEK293 cells and in hepatocyte Oc cells. Unlike the DEAD box helicases RIG-I and MDA5, DDX3 was constitutively expressed and colocalized with IPS-1 around mitochondria. In hepatocytes (O cells) with the HCV replicon, however, DDX3/IPS-1-enhanced IFN-beta-induction was largely abrogated even when DDX3 was co-expressed. DDX3 spots barely merged with IPS-1, and partly assembled in the HCV core protein located near the LD in O cells, though in some O cells IPS-1 was diminished or disseminated apart from mitochondria. Expression of DDX3 in replicon-negative or core-less replicon-positive cells failed to cause complex formation or LD association. HCV core protein and DDX3 partially colocalized only in replicon-expressing cells. Since the HCV core protein has been reported to promote HCV replication through binding to DDX3, the core protein appears to switch DDX3 from an IFN-inducing mode to an HCV-replication mode. The results enable us to conclude that HCV infection is promoted by modulating the dual function of DDX3.
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影响因子：
64.5
作者：
Dixit E;Boulant S;Zhang Y;Lee AS;Odendall C;Shum B;Hacohen N;Chen ZJ;Whelan SP;Fransen M;Nibert ML;Superti-Furga G;Kagan JC
通讯作者：
Kagan JC
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56.9
作者：
Chuang, RY;Weaver, PL;Chang, TH
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Chang, TH
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64.8
作者：
Meylan, E;Curran, J;Tschopp, R
通讯作者：
Tschopp, R
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8
作者：
Chang, PC;Chi, CW;Lee, YHW
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影响因子：
11.2
作者：
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Lee, Yan-Hwa Wu