Expression of Hepatitis C Virus Proteins Inhibits Signal Transduction through the Jak-STAT Pathway

Abstract

Hepatitis C virus (HCV) infection is a leading cause of liver disease worldwide. Alpha interferon (IFN-α) therapy of chronic hepatitis C leads to a sustained response in 10 to 20% of patients only. The mechanisms of viral persistence and the pathogenesis of hepatitis C are poorly understood. We established continuous human cell lines, allowing the tightly regulated expression of the entire HCV open reading frame under the control of a tetracycline-responsive promoter. Using this in vitro system, we analyzed the effect of HCV proteins on IFN-induced intracellular signaling. Expression of HCV proteins in these cells strongly inhibited IFN-α-induced signal transduction through the Jak-STAT pathway. Inhibition occurred downstream of STAT tyrosine phosphorylation. Inhibition of the Jak-STAT pathway was not restricted to IFN-α-induced signaling but was observed in leukemia inhibitory factor-induced signaling through Stat3 as well. By contrast, tumor necrosis factor alpha-induced activation of the transcription factor NF-κB was not affected. Interference of HCV with IFN-α-induced signaling through the Jak-STAT pathway could contribute to the resistance to IFN-α therapy observed in the majority of patients and may represent a general escape strategy of HCV contributing to viral persistence and pathogenesis of chronic liver disease.

Non-encapsidation activities of the capsid proteins of positive-strand RNA viruses

“…Perhaps no other (+)-strand virus has received more attention than HCV with regard to the innate immune responses. The HCV core protein interferes with multiple components of the signaling cascades that lead to IFN production (Arnaud et al, 2010;Bode et al, 2003;Ciccaglione et al, 2007;de Lucas et al, 2005;Garaigorta and Chisari, 2009;Heim et al, 1999;Lin et al, 2006;Oshiumi et al, 2010). The ability of HCV core protein to interact multiple components of the innate immune pathway is likely related to core protein possessing regions characterized by intrinsic disorder.…”

Characterization of the cleavage of signal peptide at the C-terminus of hepatitis C virus core protein by signal peptide peptidase

“…2). The expression level of different proteins was also quantified using software ''Quantity one'': Comparing with total intensity of processed and unprocessed proteins (as 100%), the intensity of core protein with 179 a.a. is 59.6% in HCV a.a. 1-200 with spko mutation construct (lane 6 and 7), HCV a.a. 1-240 with spko mutation (lanes 8 and 9), HCV a.a. 1-260 with spko mutation (lanes 10 and 11), HCV a.a. 1-280 with spko mutation (lanes 12 and 13), SPP inhibitor (Z(LL) 2 -ketone) was treated in lanes 3,5,7,9,11,13. After transfection, recombinant proteins were collected, subjected to SDS-PAGE analysis, followed by Western blotting assay using anti-core mAb.…”

“…In addition to its structural property, HCV core protein has been demonstrated to regulate host cellular functions in cultured cells, e.g. gene transcription [5], signal transduction [6][7][8], and apoptosis [9,10,11]. Moreover, transgenic mice with HCV core protein developed liver steatosis and thereafter hepatocellular carcinoma [12,13].…”

Early IFN type I response: Learning from microbial evasion strategies

“…However, contrasting results have been reported that probably stem from the use of different cell lines or different HCV expression/replication systems [200][201][202][203][204]. The core protein has been reported to upregulate the expression of SOCS3, thereby inhibiting tyrosine phosphorylation of STAT1 [201], although the decreased STAT1 phoshorylation has not been detected in other studies [200,205]. The HCV core protein, expressed alone, has been reported to directly bind to STAT1 and to prevent its phosphorylation and subsequent expression of downstream ISGs [206].…”