title: Matrix Metalloproteinase 9 Facilitates Hepatitis B Virus Replication through Binding with Type I Interferon (IFN) Receptor 1 To Repress IFN/JAK/STAT Signaling.
abstract: Hepatitis B virus (HBV) infection may cause acute hepatitis B, chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma (HCC). However, the mechanisms by which HBV evades host immunity and maintains chronic infection are largely unknown. Here, we revealed that matrix metalloproteinase 9 (MMP-9) is activated in peripheral blood mononuclear cells (PBMCs) of HBV-infected patients, and HBV stimulates MMP-9 expression in macrophages and PBMCs isolated from healthy individuals. MMP-9 plays important roles in the breakdown of the extracellular matrix and in the facilitation of tumor progression, invasion, metastasis, and angiogenesis. MMP-9 also regulates respiratory syncytial virus (RSV) replication, but the mechanism underlying such regulation is unknown. We further demonstrated that MMP-9 facilitates HBV replication by repressing the interferon (IFN)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, IFN action, STAT1/2 phosphorylation, and IFN-stimulated gene (ISG) expression. Moreover, MMP-9 binds to type I IFN receptor 1 (IFNAR1) and facilitates IFNAR1 phosphorylation, ubiquitination, subcellular distribution, and degradation to interfere with the binding of IFANR1 to IFN-α. Thus, we identified a novel positive-feedback regulation loop between HBV replication and MMP-9 production. On one hand, HBV activates MMP-9 in infected patients and leukocytes. On the other hand, MMP-9 facilitates HBV replication through repressing IFN/JAK/STAT signaling, IFNAR1 function, and IFN-α action. Therefore, HBV may take the advantage of MMP-9 function to establish or maintain chronic infection.IMPORTANCEHepatitis B virus (HBV) infection may cause chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). However, the mechanisms by which HBV maintains chronic infection are largely unknown. Matrix metalloproteinase 9 (MMP-9) plays important roles in the facilitation of tumor progression, invasion, metastasis, and angiogenesis. However, the effects of MMP-9 on HBV replication and pathogenesis are not known. This study reveals that MMP-9 expression is activated in patients with CHB, and HBV stimulates MMP-9 production in PBMCs and macrophages. More interestingly, MMP-9 in turn promotes HBV replication through suppressing IFN-α action. Moreover, MMP-9 interacts with type I interferon receptor 1 (IFNAR1) to disturb the binding of IFN-α to IFNAR1 and facilitate the phosphorylation, ubiquitination, subcellular distribution, and degradation of IFNAR1. Therefore, these results discover a novel role of MMP-9 in viral replication and reveal a new mechanism by which HBV evades host immunity to maintain persistent infection.
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Junbo
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Yecheng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Chunqiang
authors.initials: C
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Han
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Chengliang
authors.initials: C
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Kailang
authors.initials: K
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China mvlwu@whu.edu.cn jwu@whu.edu.cn.
authors.forename: Yingle
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, China mvlwu@whu.edu.cn jwu@whu.edu.cn.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wu
mesh_terms: D002478:Cells, Cultured; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D011485:Protein Binding; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D015398:Signal Transduction; D014779:Virus Replication
chemical_list: C507964:IFNAR1 protein, human; D053633:Receptor, Interferon alpha-beta; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: hepatitis B virus; interferon/Janus kinase/signal transducers and activators of transcription pathway; matrix metalloproteinase 9; type I IFN receptor 1