Tick-borne encephalitis virus NS4A ubiquitination antagonizes type I interferon-stimulated STAT1/2 signalling pathway

• Published in: Emerging microbes & infections Vol. 9; no. 1; pp. 714 - 726
• Main Authors: Yang, Qi, You, Jia, Zhou, Yuan, Wang, Yun, Pei, Rongjuan, Chen, Xinwen, Yang, Min, Chen, Jizheng
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2020; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Cell Line; DEAD Box Protein 58 - metabolism; Encephalitis; Encephalitis Viruses, Tick-Borne - metabolism; Encephalitis Viruses, Tick-Borne - physiology; Humans; Interferon Regulatory Factors - antagonists & inhibitors; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Interferon Type I - antagonists & inhibitors; Interferon Type I - metabolism; Interferon-beta - genetics; Interferon-beta - metabolism; Interferon-Induced Helicase, IFIH1 - metabolism; Interferon-Stimulated Gene Factor 3, gamma Subunit - metabolism; Lysine - metabolism; NS4A; Phosphorylation; Protein Interaction Domains and Motifs; Protein Multimerization; Receptors, Immunologic; Signal Transduction; src Homology Domains; STAT1; STAT1 Transcription Factor - metabolism; STAT2; STAT2 Transcription Factor - metabolism; Tick-borne encephalitis virus (TBEV); Ubiquitination; Up-Regulation; Viral Nonstructural Proteins - metabolism; STAT1; ubiquitination; NS4A; STAT2; Tick-borne encephalitis virus (TBEV)
• ISSN: 2222-1751; 2222-1751
• DOI: 10.1080/22221751.2020.1745094

Tick-borne encephalitis virus (TBEV) accounts for approximately 10,000 annual cases of severe encephalitis in Europe and Asia and causes encephalitis in humans. In this study, we demonstrate TBEV appears to activate the interferon (IFN)-β dependent on RIG-I/MDA5. Both the IFN-β accumulation and the IFN stimulated genes (ISGs) transcription greatly delay. Further studies reveal that TBEV NS4A could block the phosphorylation and dimerization of STAT1/STAT2 to affect type I and II IFN-mediated STAT signalling. Additional data indicate that the residue at K132 of TBEV NS4A could be modified by ubiquitination and this modification is necessary for the interaction of NS4A with STAT1. Dynamic ubiquitination of the NS4 protein during TBEV infection might account for delayed activation of the ISGs. These results define the TBEV NS4A as an antagonist of the IFN response, by demonstrating a correlation between the association and STAT interference. Our findings provide a foundation for further understanding how TBEV evade innate immunity and a potential viral target for intervention.