RACK1 mediates rewiring of intracellular networks induced by hepatitis C virus infection.,PLoS Pathogens

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RACK1 mediates rewiring of intracellular networks induced by hepatitis C virus infection.
PLoS Pathogens ( IF 5.5 ) Pub Date : 2019-09-16 , DOI: 10.1371/journal.ppat.1008021
Jae Seung Lee ₁ , Keisuke Tabata ₂ , Woan-Ing Twu ₂ , Md Shafiqur Rahman ₃ , Hee Sun Kim ₁ , Jin Bae Yu ₃ , Min Hyeok Jee ₃ , Ralf Bartenschlager _{2,

4} , Sung Key Jang _{1,

3}

Affiliation

Hepatitis C virus (HCV) is a positive-strand RNA virus replicating in a membranous replication organelle composed primarily of double-membrane vesicles (DMVs) having morphological resemblance to autophagosomes. To define the mechanism of DMV formation and the possible link to autophagy, we conducted a yeast two-hybrid screening revealing 32 cellular proteins potentially interacting with HCV proteins. Among these was the Receptor for Activated Protein C Kinase 1 (RACK1), a scaffolding protein involved in many cellular processes, including autophagy. Depletion of RACK1 strongly inhibits HCV RNA replication without affecting HCV internal ribosome entry site (IRES) activity. RACK1 is required for the rewiring of subcellular membranous structures and for the induction of autophagy. RACK1 binds to HCV nonstructural protein 5A (NS5A), which induces DMV formation. NS5A interacts with ATG14L in a RACK1 dependent manner, and with the ATG14L-Beclin1-Vps34-Vps15 complex that is required for autophagosome formation. Both RACK1 and ATG14L are required for HCV DMV formation and viral RNA replication. These results indicate that NS5A participates in the formation of the HCV replication organelle through interactions with RACK1 and ATG14L.

中文翻译：

RACK1 介导由丙型肝炎病毒感染引起的细胞内网络的重新布线。

丙型肝炎病毒 (HCV) 是一种在膜复制细胞器中复制的正链 RNA 病毒，该细胞器主要由形态与自噬体相似的双膜囊泡 (DMV) 组成。为了确定 DMV 形成的机制和与自噬的可能联系，我们进行了酵母双杂交筛选，揭示了 32 种可能与 HCV 蛋白相互作用的细胞蛋白。其中包括活化蛋白 C 激酶 1 (RACK1) 受体，这是一种参与包括自噬在内的许多细胞过程的支架蛋白。RACK1 的消耗强烈抑制 HCV RNA 复制而不影响 HCV 内部核糖体进入位点 (IRES) 活性。RACK1 是亚细胞膜结构重新布线和诱导自噬所必需的。RACK1 与 HCV 非结构蛋白 5A (NS5A) 结合，诱导 DMV 形成。NS5A 以依赖于 RACK1 的方式与 ATG14L 相互作用，并与自噬体形成所需的 ATG14L-Beclin1-Vps34-Vps15 复合物相互作用。RACK1 和 ATG14L 都是 HCV DMV 形成和病毒 RNA 复制所必需的。这些结果表明，NS5A 通过与 RACK1 和 ATG14L 的相互作用参与了 HCV 复制细胞器的形成。

更新日期：2019-09-16

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