SENP3-mediated host defense response contains HBV replication and restores protein synthesis

Rui Xi,Xiling Shen,Botao Liu,Yan Han,Shu-Bing Qian,Anastasia Varanko,Ji Wan,Yongning Xin,Xiaodong Li,Kuei-Ling Tung,Cynthia D Guy,Feng Li,Zhuo Wang,Lishan Su,Nikolai Rakhilin,Preetish Kadur Lakshminarasimha Murthy

doi:10.1371/journal.pone.0209179

Abstract

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.

Highlights

Hepatitis B virus (HBV) causes hepatitis B, a liver infectious disease affecting a significant population of people worldwide[1]
Upon HBV infection, hepatocytes downregulate SENP3 to SUMOylate and degrade IQ motif containing GTPase activating protein 2 (IQGAP2), a Ras GTPase-activating-like protein we identified as a new SENP3 substrate
Reverse-Transcription Quantitative PCR (RT-qPCR) and immunoblotting showed that SENP3 decreased significantly in HepG2-NTCP cells after HBV infection compared with HepG2-NTCP cells that had mock infection as control (Fig 1A and 1B, S1 Fig)

Summary

Introduction

Hepatitis B virus (HBV) causes hepatitis B, a liver infectious disease affecting a significant population of people worldwide[1]. The immune system is often credited with containment and clearance of HBV[4]; infected hepatocytes produce varying amounts of HBV virus, estimated to be as low as 1–10 virions per day by some reports[5, 6] Host factors such as the SMC5/6 complex have been identified to restrict HBV transcription, but HBV regulatory protein X (HBx) targets the complex for degradation, removing the obstacle[7, 8]. SUMOylation is a highly dynamic post-translational modification process reversible by SUMO-specific peptidases (SENPs), a family of proteases that catalyze de-conjugation of SUMO proteins (de-SUMOylation) [9, 10] Both SUMOylation and de-SUMOylation play important roles in cellular processes such as DNA replication and repair, cell division, apoptosis, cancer and stress responses[11,12,13,14,15]. SENP3 is a dual-faceted regulator of cell survival and growth, enhancing cell proliferation under low level of ROS while promoting cell apoptosis under high level of ROS[18, 19]

Methods

Results

Conclusion