Hepatitis B Virus e antigen activates the suppressor of cytokine signaling 2 to repress interferon action

Yi Yu, Pin Wan, Yanhua Cao, Wei Zhang, Junbo Chen, Li Tan, Yan Wang, Zhichen Sun, Qi Zhang, Yushun Wan, Ying Zhu, Fang Liu, Kailang Wu, Yingle Liu, Jianguo Wu

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10 Scopus citations

Abstract

Hepatitis B virus (HBV) infection causes acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), and eventually hepatocellular carcinoma (HCC). The presence of hepatitis B e antigen (HBeAg) in the serum generally indicates ongoing viral replication and disease progression. However, the mechanism by which HBeAg regulates HBV infection remains unclear. Interferons (IFNs) are pleiotropic cytokines that participate in host innate immunity. After binding to receptors, IFNs activate the JAK/STAT pathway to stimulate expression of IFN-stimulated genes (ISGs), leading to induction of antiviral responses. Here, we revealed that HBeAg represses IFN/JAK/STAT signaling to facilitate HBV replication. Initially, HBeAg stimulates the expression of suppressor of cytokine signaling 2 (SOCS2). Subsequently, SOCS2 impairs IFN/JAK/STAT signaling through reducing the stability of tyrosine kinase 2 (TYK2), downregulating the expression of type I and III IFN receptors, attenuating the phosphorylation and nucleus translocation of STAT1. Finally, SOCS2 inhibits the expression of ISGs, which leads to the repression of IFN action and facilitation of viral replication. These results demonstrate an important role of HBeAg in the regulation of IFN action, and provide a possible molecular mechanism by which HBV resists the IFN therapy and maintains persistent infection.

Original languageEnglish (US)
Article number1729
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

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    Yu, Y., Wan, P., Cao, Y., Zhang, W., Chen, J., Tan, L., Wang, Y., Sun, Z., Zhang, Q., Wan, Y., Zhu, Y., Liu, F., Wu, K., Liu, Y., & Wu, J. (2017). Hepatitis B Virus e antigen activates the suppressor of cytokine signaling 2 to repress interferon action. Scientific reports, 7(1), [1729]. https://doi.org/10.1038/s41598-017-01773-6