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Theranostics 2020; 10(26):12223-12240. doi:10.7150/thno.50992 This issue Cite

Research Paper

Virus-induced p38 MAPK activation facilitates viral infection

Yuting Cheng^1,2#, Fang Sun^1#, Luyao Wang¹, Minjun Gao¹, Youli Xie³, Yu Sun⁴, Huan Liu³, Yufeng Yuan³, Wei Yi⁵, Zan Huang¹, Huan Yan¹, Ke Peng⁶, Yingliang Wu¹, Zhijian Cao^1,7✉

1. State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, China.
2. Jiangsu Agri-animal Husbandry Vocational College, Jiangsu Key Laboratory for High-Tech Research and Development of Veterinary Biopharmaceuticals, Taizhou, 225300, China.
3. Zhongnan Hospital of Wuhan University, Wuhan 430071, Wuhan 430072, Hubei, China.
4. School of Medicine, Wuhan University of Science and Technology, Wuhan 430065, Hubei, China.
5. Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China.
6. Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, Hubei, China.
7. Hubei Province Engineering and Technology Research, Center for Fluorinated Pharmaceuticals, Wuhan University, Wuhan 430071, Hubei, China.
#These authors contributed equally to this work.

✉ Corresponding author: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, China. Tel: +86-27-68752831, Fax: +86-27-68756746. E-mail: zjcaoedu.cn (Zhijian Cao).

Abstract

Rationale: Many viral infections are known to activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway. However, the role of p38 activation in viral infection and the underlying mechanism remain unclear. The role of virus-hijacked p38 MAPK activation in viral infection was investigated in this study.

Methods: The correlation of hepatitis C virus (HCV) infection and p38 activation was studied in patient tissues and primary human hepatocytes (PHHs) by immunohistochemistry and western blotting. Coimmunoprecipitation, GST pulldown and confocal microscopy were used to investigate the interaction of p38α and the HCV core protein. In vitro kinase assays and mass spectrometry were used to analyze the phosphorylation of the HCV core protein. Plaque assays, quantitative real time PCR (qRT-PCR), western blotting, siRNA and CRISPR/Cas9 were used to determine the effect of p38 activation on viral replication.

Results: HCV infection was associated with p38 activation in clinical samples. HCV infection increased p38 phosphorylation by triggering the interaction of p38α and TGF-β activated kinase 1 (MAP3K7) binding protein 1 (TAB1). TAB1-mediated p38α activation facilitated HCV replication, and pharmaceutical inhibition of p38α activation by SB203580 suppressed HCV infection at the viral assembly step. Activated p38α interacted with the N-terminal region of the HCV core protein and subsequently phosphorylated the HCV core protein, which promoted HCV core protein oligomerization, an essential step for viral assembly. As expected, SB203580 or the HCV core protein N-terminal peptide (CN-peptide) disrupted the p38α-HCV core protein interaction, efficiently impaired HCV assembly and impeded normal HCV replication in both cultured cells and primary human hepatocytes. Similarly, severe fever with thrombocytopenia syndrome virus (SFTSV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection also activated p38 MAPK. Most importantly, pharmacological blockage of p38 activation by SB203580 effectively inhibited SFTSV, HSV-1 and SARS-CoV-2.

Conclusion: Our study shows that virus-hijacked p38 activation is a key event for viral replication and that pharmacological blockage of p38 activation is an antiviral strategy.

Keywords: P38 activation, TAB1, HCV, SFTSV, SARS-CoV-2

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