High-mobility group box 1 (HMGB1), an abundant nuclear protein that triggers host immune responses, is an endogenous danger signal involved in the pathogenesis of various infectious agents. However, its role in hepatitis C virus (HCV) infection is not known. Here, we show that HMGB1 protein is translocated from the nucleus to cytoplasm and subsequently is released into the extracellular milieu by HCV infection. Secreted HMGB1 triggers antiviral responses and blocks HCV infection, a mechanism that may limit HCV propagation in HCV patients. Secreted HMGB1 also may have a role in liver cirrhosis, which is a common comorbidity in HCV patients. Further investigations into the roles of HMGB1 in the diseases caused by HCV infection will shed light on and potentially help prevent these serious and prevalent HCV-related diseases.Hepatitis C virus (HCV) is one of the major causative agents of hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) (17, 30). More than 170 million people are estimated to suffer from HCV infection worldwide (17). Chronic and persistent infection is a characteristic feature of HCV pathogenesis (30). During chronic infection, the production of virus particles is limited, and a restricted number of liver cells are infected. As a result, the viral dose in patients' blood generally is lower than that of other hepatitis-causing viruses, such as hepatitis B virus (HBV) (4). Moreover, a large portion of hepatocytes often remains uninfected by the virus even after long-term infection (28). These phenomena indicate the existence of balance between the HCV infection process and host mechanisms that protect against HCV infection. We speculate that innate and adaptive immunities contribute to the balance between infection and protection.High-mobility group box 1 (HMGB1) protein is a highly conserved nuclear protein that participates in DNA organization and the regulation of transcription. In addition to its nuclear function, HMGB1 plays an important role as a cytokine, mediating the responses to infection, injury, and inflammation (1, 2, 29, 42). HMGB1 is released passively from necrotic cells and is actively secreted from activated immune cells, such as macrophages, natural killer cells, and mature dendritic cells (2). The functionality of actively secreted HMGB1 is known to be modulated by posttranslational modifications, such as oxidation (2, 36). Extracellular HMGB1 can function by itself and/or in association with other molecules, including CpG DNA, lipopolysaccharide (LPS), and interleukin-1 (IL-1) (5). HMGB1 induces a variety of cellular responses that contribute to innate immunity, tissue repair, and cell migration through interactions with various receptors that activate multiple signal transduction responses. The Toll-like receptors (e.g., TLR2, TLR4, and TLR9) and the receptor for advanced glycation end products (RAGE) are known receptors for the cytokine functions of HMGB1 (2). TLR4, the major component of the LPS recognition receptor complex, engages in downstream signaling through My...
Hepatic fibrosis is a critical step in liver cirrhosis caused by hepatitis C virus infection. It is already known that immune cells, including Kupffer cells, mediate liver fibrosis. Recently, several papers have suggested that HCV-infected hepatocytes also significantly produce TGF-β1. Here, we provide the first examination of TGF-β1 levels in the hepatocytes of HCV patients. Using an HCV culture system, we showed that HCV infection increases TGF-β1 production in hepatocytes. Furthermore, we confirmed that the amount of TGF-β1 secreted by HCV-infected hepatocytes was sufficient to activate primary hepatic stellate cells. To understand the molecular basis of TGF-β1 production in HCV-infected hepatocytes, we used HCV replicons and various stable cell lines. Finally, we elucidated that HCV E2 triggered TGF-β1 secretion via GRP94 mediated NF-κB activation. This study contributes to the understanding of liver fibrosis by HCV and suggests a new potential target (GRP94) for blocking liver cirrhosis in HCV patients.
Various forms of hepatitis C virus (HCV)-related particles are produced from HCV-infected cells. Measuring infectivity of a HCV sample with the conventional 'foci counting method' is laborious and time-consuming. Moreover, the infectivity of a HCV sample does not correlate with the amount of viral RNA that can be measured by real-time RT-PCR. Here we report a new assay suitable for quantifying infectious HCV particles using aptamers against HCV E2, which is named 'Enzyme Linked Apto-Sorbent Assay (ELASA)'. The readout value of HCV ELASA linearly correlates with the infectious dose of an HCV sample, but not with the amount of HCV RNA. We also demonstrated that the activities of anti-HCV drugs can be monitored by HCV ELASA. Therefore, HCV ELASA is a quick-and-easy method to quantify infectious units of HCV stocks and to monitor efficacies of potential anti-HCV drugs.
Hepatitis C virus (HCV) is a positive-strand RNA virus replicating in a membranous replication organelle composed primarily of double-membrane vesicles (DMVs) having morphological resemblance to autophagosomes. To define the mechanism of DMV formation and the possible link to autophagy, we conducted a yeast two-hybrid screening revealing 32 cellular proteins potentially interacting with HCV proteins. Among these was the Receptor for Activated Protein C Kinase 1 (RACK1), a scaffolding protein involved in many cellular processes, including autophagy. Depletion of RACK1 strongly inhibits HCV RNA replication without affecting HCV internal ribosome entry site (IRES) activity. RACK1 is required for the rewiring of subcellular membranous structures and for the induction of autophagy. RACK1 binds to HCV nonstructural protein 5A (NS5A), which induces DMV formation. NS5A interacts with ATG14L in a RACK1 dependent manner, and with the ATG14L-Beclin1-Vps34-Vps15 complex that is required for autophagosome formation. Both RACK1 and ATG14L are required for HCV DMV formation and viral RNA replication. These results indicate that NS5A participates in the formation of the HCV replication organelle through interactions with RACK1 and ATG14L.
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