Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Cell Infect Microbiol. 2018 Apr 4;8:109. doi: 10.3389/fcimb.2018.00109. eCollection 2018.
Autophagy is a host mechanism for cellular homeostatic control. Intracellular stresses are symptoms of, and responses to, dysregulation of the physiological environment of the cell. Alternative gene transcription splicing is a mechanism potentially used by a host to respond to physiological or pathological challenges. Here, we aimed to confirm opposite effects of two isoforms of the human autophagy-related protein ATG10 on an HCV subgenomic replicon in zebrafish. A liver-specific HCV subreplicon model was established and exhibited several changes in gene expression typically induced by HCV infection, including overexpression of several HCV-dependent genes (, and ), as well as overexpression of several ER stress related genes (, and ). Autophagy flux was blocked in the HCV model. Our results indicated that the replication of the HCV subreplicon was suppressed via a decrease in autophagosome formation caused by the autophagy inhibitor 3MA, but enhanced via dysfunction in the lysosomal degradation caused by another autophagy inhibitor CQ. Human ATG10, a canonical isoform in autophagy, facilitated the amplification of the HCV-subgenomic replicon via promoting autophagosome formation. ATG10S, a non-canonical short isoform of the ATG10 protein, promoted autophagy flux, leading to lysosomal degradation of the HCV-subgenomic replicon. Human ATG10S may therefore inhibit HCV replication, and may be an appropriate target for future antiviral drug screening.
自噬是细胞内稳态控制的一种宿主机制。细胞内应激是细胞生理环境失调的症状和反应。替代基因转录剪接是宿主应对生理或病理挑战时可能使用的一种机制。在这里，我们旨在证实两种人类自噬相关蛋白 ATG10 的同工型对斑马鱼 HCV 亚基因组复制子的相反作用。建立了一个肝脏特异性 HCV 亚复制子模型，该模型表现出几种通常由 HCV 感染诱导的基因表达变化，包括几种 HCV 依赖性基因（、和）以及几种 ER 应激相关基因（、和）的过表达。HCV 模型中的自噬流被阻断。我们的结果表明，通过自噬抑制剂 3MA 引起的自噬体形成减少，抑制了 HCV 亚复制子的复制，但通过另一种自噬抑制剂 CQ 引起的溶酶体降解功能障碍增强了其复制。人类 ATG10 是自噬中的一种规范同工型，通过促进自噬体形成促进了 HCV 亚基因组复制子的扩增。ATG10S 是 ATG10 蛋白的非规范短同工型，促进了自噬流，导致 HCV 亚基因组复制子的溶酶体降解。因此，人类 ATG10S 可能抑制 HCV 复制，可能是未来抗病毒药物筛选的合适靶点。
