Production of a dominant-negative fragment due to G3BP1 cleavage contributes to the disruption of mitochondria-associated protective stress granules during CVB3 infection.
Production of a dominant-negative fragment due to G3BP1 cleavage contributes to the disruption of mitochondria-associated protective stress granules during CVB3 infection.
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DOI：
10.1371/journal.pone.0079546
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Luo H
中科院分区：
文献类型：
--
作者：
Fung G;Ng CS;Zhang J;Shi J;Wong J;Piesik P;Han L;Chu F;Jagdeo J;Jan E;Fujita T;Luo H
应激颗粒（Stress granules，SG）是一种含有信使核糖核蛋白和靶多聚腺苷酸（poly-adenylated，A）-mRNA的动态胞质聚集体。SGs的一个关键组分是Ras-GAP SH 3结构域结合蛋白-1（G3 BP 1），其部分介导蛋白质-蛋白质和蛋白质-RNA相互作用。在感染过程中，几种病毒调节SG，然而，这一过程的功能和意义仍然知之甚少。在这项研究中，我们研究了SGs和柯萨奇病毒B3型（CVB 3），小核糖核酸病毒科的成员之间的相互作用。我们的研究表明，SGs在CVB 3感染早期形成;然而，G3 BP 1阳性的SGs在感染后5小时被主动分解，而poly（A）阳性的RNA颗粒持续存在。此外，我们证实了3Cpro在Q325处切割G3 BP 1。我们还证明了G3 BP 1-SGs的过表达在RNA、蛋白质和病毒子代水平上对病毒复制产生负面影响。使用电子显微镜技术，我们发现，G3 BP 1阳性SGs定位于线粒体表面附近。最后，我们提供的证据表明，G3 BP 1的C-末端切割产物抑制SG的形成和促进CVB 3的复制。综上所述，我们得出结论，CVB 3感染通过切割G3 BP 1产生显性负性片段，进一步抑制G3 BP 1-SG形成并促进病毒复制，从而选择性地靶向G3 BP 1-SG。
Stress granules (SGs) are dynamic cytosolic aggregates containing messenger ribonucleoproteins and target poly-adenylated (A)-mRNA. A key component of SGs is Ras-GAP SH3 domain binding protein-1 (G3BP1), which in part mediates protein-protein and protein-RNA interactions. SGs are modulated during infection by several viruses, however, the function and significance of this process remains poorly understood. In this study, we investigated the interplay between SGs and Coxsackievirus type B3 (CVB3), a member of the Picornaviridae family. Our studies demonstrated that SGs were formed early during CVB3 infection; however, G3BP1-positive SGs were actively disassembled at 5 hrs post-infection, while poly(A)-positive RNA granules persisted. Furthermore, we confirmed G3BP1 cleavage by 3Cpro at Q325. We also demonstrated that overexpression of G3BP1-SGs negatively impacted viral replication at the RNA, protein, and viral progeny levels. Using electron microscopy techniques, we showed that G3BP1-positive SGs localized near mitochondrial surfaces. Finally, we provided evidence that the C-terminal cleavage product of G3BP1 inhibited SG formation and promoted CVB3 replication. Taken together, we conclude that CVB3 infection selectively targets G3BP1-SGs by cleaving G3BP1 to produce a dominant-negative fragment that further inhibits G3BP1-SG formation and facilitates viral replication.
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