Hepatic expression of proteasome subunit alpha type‐6 is upregulated during viral hepatitis and putatively regulates the expression of ISG15 ubiquitin‐like modifier, a proviral host gene in hepatitis C virus infection

Abstract

The interferon-stimulated gene 15 (ISG15) plays an important role in the pathogenesis of hepatitis C virus (HCV) infection. ISG15-regulated proteins have previously been identified that putatively affect this proviral interaction. The present observational study aimed to elucidate the relation between ISG15 and these host factors during HCV infection. Transcriptomic and proteomic analyses were performed using liver samples of HCV-infected (n = 54) and uninfected (n = 10) or HBV-infected controls (n = 23). Primary human hepatocytes (PHH) were treated with Toll-like receptor ligands, interferons and kinase inhibitors. Expression of ISG15 and proteasome subunit alpha type-6 (PSMA6) was suppressed in subgenomic HCV replicon cell lines using specific siRNAs. Comparison of hepatic expression patterns revealed significantly increased signals for ISG15, IFIT1, HNRNPK and PSMA6 on the protein level as well as ISG15, IFIT1 and PSMA6 on the mRNA level in HCV-infected patients. In contrast to interferon-stimulated genes, PSMA6 expression occurred independent of HCV load and genotype. In PHH, the expression of ISG15 and PSMA6 was distinctly induced by poly(I:C), depending on IRF3 activation or PI3K/AKT signalling, respectively. Suppression of PSMA6 in HCV replicon cells led to significant induction of ISG15 expression, thus combined knock-down of both genes abrogated the antiviral effect induced by the separate suppression of ISG15. These data indicate that hepatic expression of PSMA6, which is upregulated during viral hepatitis, likely depends on TLR3 activation. PSMA6 affects the expression of immunoregulatory ISG15, a proviral factor in the pathogenesis of HCV infection. Therefore, the proteasome might be involved in the enigmatic interaction between ISG15 and HCV.

Interferon-stimulated gene 15 in hepatitis B-related liver diseases

“…In contrast, our study showed that ISG15 levels were positively correlated with viral loads, implying a contradictory effect of ISG15 on antiviral activities. This is consistent with studies showing that ISG15 can promote HCV replication [ 19 , 35 , 36 ].…”

“…ISG15 plays also a role in the response to many viral infections [9,15-18]. A recent study has shown that knockdown of ISG15 results in suppression of hepatitis C virus (HCV) replication in vitro by promoting the IFN response, suggesting involvement of ISG15 in regulating HCV replication [19,20]. Furthermore, patients who respond favorably to IFN treatment of hepatitis C have low expression levels of ISG15 and its conjugates in the liver compared to non-responders [21,22].…”

Organizing gene literature retrieval, profiling, and visualization training workshops for early career researchers

“…14 In addition, high levels of ISG15 in the liver of patients with HCV infection were associated with an unfavourable HCV genotype 1, a high hepatic HCV load and a low antiviral response to IFN compared to patients who did not present such characteristics. 13 These findings indicate the potential of ISG15 as a biomarker of IFN treatment response in patients with HCV infection.…”

“…12 Furthermore, upregulated expression of ISG15 was observed at both the mRNA and protein levels in liver tissue samples from patients with HCV infection compared to the levels detected in uninfected controls. 13 Similarly, the abundance of ISG15 transcripts was found to be increased in human PBMCs and liver cells in patients with HCV infection who were unresponsive to IFN treatment compared to the levels in corresponding IFN-responsive patients. 14 In addition, high levels of ISG15 in the liver of patients with HCV infection were associated with an unfavourable HCV genotype 1, a high hepatic HCV load and a low antiviral response to IFN compared to patients who did not present such characteristics.…”

Elevated Expression of Chemokine CXCL13 in Chronic Hepatitis B Patients Links to Immune Control during Antiviral Therapy

“…Boltjes et al (29) demonstrated that a direct interaction between HBsAg and KC resulted in HBsAg uptake, induction of cytokine production, and the induction of IFN-γ production by NK cells. Alternatively, phagocytosis of HBV itself or -infected hepatocytes by KC may allow intracellular TLR3 exposure to viral RNA (30, 31). …”