Protein Inhibitor of Activated STAT2 Restricts HCV Replication by Modulating Viral Proteins Degradation.

Jing Guo,Xiaoxiao Gao,Dan Chen,Chunchen Wu,Yun Wang,Jizheng Chen,Rongjuan Pei,Yuan Zhou,Xue Hu,Xinwen Chen

doi:10.3390/v9100285

Abstract

Hepatitis C virus (HCV) replication in cells is controlled by many host factors. In this report, we found that protein inhibitor of activated STAT2 (PIAS2), which is a small ubiquitin-like modifier (SUMO) E3 ligase, restricted HCV replication. During infection, HCV core, NS3 and NS5A protein expression, as well as the viral assembly and budding efficiency were enhanced when endogenous PIAS2 was knocked down, whereas exogenous PIAS2 expression decreased HCV core, NS3, and NS5A protein expression and the viral assembly and budding efficiency. PIAS2 did not influence the viral entry, RNA replication, and protein translation steps of the viral life cycle. When expressed together with SUMO1, PIAS2 reduced the HCV core, NS3 and NS5A protein levels expressed from individual plasmids through the proteasome pathway in a ubiquitin-independent manner; the stability of these proteins in the HCV infectious system was enhanced when PIAS2 was knocked down. Furthermore, we found that the core was SUMOylated at amino acid K78, and PIAS2 enhanced the SUMOylation level of the core.

Highlights

Hepatitis C virus (HCV) is one of the major causes of chronic liver disease and is an enveloped, positive-strand RNA virus that belongs to the Flaviviridae family [1]
Levels were similar in the siPIAS2—and siNC—transfected cells (Figure 1A), an obvious increase in the HCV core, NS3 and NS5A protein but not the NS4B protein levels was observed in the siPIAS2 transfected cells (Figure 1B)
Subgenomic replicon cell line, we determined that protein inhibitor of activated STAT2 (PIAS2) functioned in the HCV core, NS3 and NS5A

Summary

Introduction

Hepatitis C virus (HCV) is one of the major causes of chronic liver disease and is an enveloped, positive-strand RNA virus that belongs to the Flaviviridae family [1]. RNA, the HCV polyprotein is cleaved by host and viral proteases into ten viral proteins, including structural proteins (core, E1 and E2) and nonstructural proteins The nonstructural proteins form the replication complex and coordinate viral RNA replication. NS3 is a multifunctional protein with serine protease and RNA helicase activities, and NS5A interacts with other viral and cellular proteins and functions in viral replication and assembly. NS3, NS5A and the NS5B RNA-dependent RNA polymerase (RdRp) are targets for anti-viral drug development. Intracellular membranes are rearranged to form so-called membranous web structures [3], and lipid droplet numbers are increased and accumulated [4]; these processes are required for HCV replication and assembly, respectively. Host cells have developed tactics to restrain viral replication.

Methods

Results

Conclusion