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-␣. 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-␣ action. Therefore, HBV may take the advantage of MMP-9 function to establish or maintain chronic infection. IMPORTANCE Hepatitis 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-␣ action. Moreover, MMP-9 interacts with type I interferon receptor 1 (IFNAR1) to disturb the binding of IFN-␣ 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.KEYWORDS hepatitis B virus, interferon/Janus kinase/signal transducers and activators of transcription pathway, matrix metalloproteinase 9, type I IFN receptor 1

Liver macrophages: Friend or foe during hepatitis B infection?

“…Moreover, Chen et al. have shown that the matrix metalloproteinase 9 (MMP‐9) is up‐regulated in PBMCs of chronic hepatitis B patients and can be activated by HBV in PBMCs and macrophages in vitro . This up‐regulation may favour the infection as the authors further showed that MMP‐9 enhanced HBV replication in hepatocytes through binding to IFNAR1 (IFNα receptor 1), inducing its ubiquitinylation and degradation (Figure , path#2).…”

SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation

“…HBV core-associated DNA was purified according to the protocol described in our previous study [18]. In brief, the cells were lysed in lysis buffer (50 mM Tris-HCl [pH 7.0], 0.5% NP-40) on ice and centrifuged for 1 min at 10,000× g. The supernatant was treated with 10 mM MgCl2 and DNaseI for 1 h at 37 • C. Protein was digested with proteinase K and 1% SDS overnight.…”

LncRNA expression profiles in HBV‐transformed human hepatocellular carcinoma cells treated with a novel inhibitor of human La protein

“…The top ten enriched pathways were the Jak‐STAT signalling pathway, the p53 signalling pathway, apoptosis and the role of mitochondria in apoptotic signalling (Figure B). All of these pathways are closely associated with HBV infection or cell apoptosis. It appears that upon treatment with H11, the differentially expressed lncRNAs were enriched in apoptotic‐related pathways resulting in suppression of the replication and spread of HBV.…”

“…Pathway analysis of lncRNAs identified the Jak‐STAT signalling pathway, the p53 signalling pathway, apoptosis and the cytochrome c‐mediated apoptotic response. It has been demonstrated that repression of Jak‐STAT signalling is beneficial to HBV replication …”