Interferon-Stimulated Gene 15 Conjugation Stimulates Hepatitis B Virus Production Independent of Type I Interferon Signaling PathwayIn Vitro

Abstract

Hepatitis B virus (HBV) is an important account of infectious hepatitis and interferon (IFN) remains one of the best treatment options. Activation of type I IFN signaling pathway leads to expressions of IFN-stimulated genes (ISGs) which play important roles in antiviral and immunomodulatory responses to HBV or hepatitis C virus (HCV) infection. Our previous studies indicated that ISG15 and its conjugation (ISGylation) were exploited by HCV to benefit its replication and persistent infection. This study was designed to assess the role of ISG15 and ISGylation in HBV infection in vitro. The levels of ISG15 and ISGylation were upregulated by ISG15 plasmid transfection into HepG2.2.15 cells. Decreased ISGylation was achieved by siRNA targeting UBE1L, the only E1 activating enzyme for ISGylation. Overexpression of ISG15 and subsequent ISGylation significantly increased the levels of HBV DNA in the culture supernatants although the intracellular viral replication remained unaffected. Silencing UBE1L, with decreased ISGylation achieved, abrogated this ISGylation-mediated promoting effect. Our data indicated that overexpression of ISG15 stimulated HBV production in an ISGylation-dependent manner. Identification of ISG15-conjugated proteins (either HBV viral or host proteins) may reveal promising candidates for further antiviral drug development.

Severe fever with thrombocytopenia syndrome virus inhibits exogenous Type I IFN signaling pathway through its NSs in vitro

“…ISG12a can inhibit HCV replication through activation of the JAK/STAT signaling pathway[ 43 ]. A recent study has found that ISG15 conjugation can stimulate Hepatitis B Virus(HBV)production independent of Type I IFN signaling pathway[ 44 ]. All these data point out virus-host interaction is of tremendous importance in the battle against virus infection.…”

ISG15 in antiviral immunity and beyond

“…Viral release: for specific viruses, ISG15 was found to modulate the amount of released infectious viral particles while intracellular viral replication remains intact. Interestingly , whereas the molecular mechanism is unclear, such effects can be either antiviral (for example, dengue virus 2 (DENV-2)) 156 or proviral (for example, hepatitis B virus (HBV)) 157 depending on the type of virus. Viral latency: ISG15 was also shown to maintain viral latency and prevent reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) infection via the regulation of specific KSHV microRNAs 74,158 with a cytokine storm, and the survival of Isg15 −/− mice could be prolonged when they were treated with TNFα-blocking antibody before infection 76 .…”

Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway

“…HCV has also been described to use ISGylation to favor its replication and develop persistent infections [ 213 , 214 ]. Recently, ISGylation was also associated with increased replication in HBV infections [ 215 ].…”