Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, North Carolina, United States of America.
Duke Center for Genomic and Computational Biology, Duke University, Durham, North Carolina, United States of America.
PLoS One. 2019 Jan 14;14(1):e0209179. doi: 10.1371/journal.pone.0209179. eCollection 2019.
Certain organs are capable of containing the replication of various types of viruses. In the liver, infection of Hepatitis B virus (HBV), the etiological factor of Hepatitis B and hepatocellular carcinoma (HCC), often remains asymptomatic and leads to a chronic carrier state. Here we investigated how hepatocytes contain HBV replication and promote their own survival by orchestrating a translational defense mechanism via the stress-sensitive SUMO-2/3-specific peptidase SENP3. We found that SENP3 expression level decreased in HBV-infected hepatocytes in various models including HepG2-NTCP cell lines and a humanized mouse model. Downregulation of SENP3 reduced HBV replication and boosted host protein translation. We also discovered that IQGAP2, a Ras GTPase-activating-like protein, is a key substrate for SENP3-mediated de-SUMOylation. Downregulation of SENP3 in HBV infected cells facilitated IQGAP2 SUMOylation and degradation, which leads to suppression of HBV gene expression and restoration of global translation of host genes via modulation of AKT phosphorylation. Thus, The SENP3-IQGAP2 de-SUMOylation axis is a host defense mechanism of hepatocytes that restores host protein translation and suppresses HBV gene expression.
某些器官能够控制各种类型病毒的复制。在肝脏中，乙型肝炎病毒（HBV）的感染——乙型肝炎和肝细胞癌（HCC）的病因，通常无症状，并导致慢性携带者状态。在这里，我们研究了肝细胞如何通过应激敏感的 SUMO-2/3 特异性肽酶 SENP3 协调翻译防御机制来包含 HBV 复制并促进自身存活。我们发现，在 HepG2-NTCP 细胞系和人源化小鼠模型等各种模型中，HBV 感染的肝细胞中的 SENP3 表达水平降低。SENP3 的下调减少了 HBV 的复制并促进了宿主蛋白的翻译。我们还发现，IQGAP2，一种 Ras GTPase 激活样蛋白，是 SENP3 介导的去 SUMO 化的关键底物。HBV 感染细胞中 SENP3 的下调促进了 IQGAP2 的 SUMO 化和降解，这导致通过调节 AKT 磷酸化来抑制 HBV 基因表达和恢复宿主基因的整体翻译。因此，SENP3-IQGAP2 去 SUMO 化轴是肝细胞的宿主防御机制，它恢复宿主蛋白的翻译并抑制 HBV 基因的表达。
