Interferon-stimulated gene ISG12b2 is localized to the inner mitochondrial membrane and mediates virus-induced cell death

Abstract

Interferons (IFNs) are crucial for host defence against viruses. Many IFN-stimulated genes (ISGs) induced by viral infection exert antiviral effects. Microarray analysis of gene expression induced in liver tissues of mice on dengue virus (DENV) infection has led to identification of the ISG gene ISG12b2. ISG12b2 is also dramatically induced on DENV infection of Hepa 1-6 cells (mouse hepatoma cell line). Here, we performed biochemical and functional analyses of ISG12b2. We demonstrate that ISG12b2 is an inner mitochondrial membrane (IMM) protein containing a cleavable mitochondrial targeting sequence and multiple transmembrane segments. Overexpression of ISG12b2 in Hepa 1-6 induced release of cytochrome c from mitochondria, disruption of the mitochondrial membrane potential, and activation of caspase-9, caspase-3, and caspase-8. Treatment of ISG12b2-overexpressing Hepa 1-6 with inhibitors of pan-caspase, caspase-9, or caspase-3, but not caspase-8, reduced apoptotic cell death, suggesting that ISG12b2 activates the intrinsic apoptotic pathway. Of particular interest, we further demonstrated that ISG12b2 formed oligomers, and that ISG12b2 was able to mediate apoptosis through both Bax/Bak-dependent and Bax/Bakindependent pathways. Our study demonstrates that the ISG12b2 is a novel IMM protein induced by IFNs and regulates mitochondria-mediated apoptosis during viral infection. Cell Death and Differentiation (2011) 18, 925-936; doi:10.1038/cdd.2010.160; published online 10 December 2010Type I interferons (IFNs) are the best-known molecules critical for the resistance to viral infection and the regulation of immune response in host defence against viral infection.

Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients

“…rather, it acts by inducing IFN-stimulated genes, which establish a non-virus-specific antiviral state within the cell (Lu & Liao 2011). Pawlotsky et al (2004) reassessed the effects of rBV monotherapy on early viral kinetics and found that rBV led to a small, early and transient reduction in HCV viraemia in a proportion of patients.…”

Hfe-associated steatohepatitis: expression profiling and identifying the molecular basis of liver injury

“…Ifi27l2b, is an interferon stimulated gene and its overexpression has induced apoptosis in a mouse tumour cell line (215). Hepatic Ifi27l2b gene expression was found significantly increased in Hfe -/-mice fed a HCD and consistent with the results of gene expression studies, an increase in IFI27L2B protein was also observed in these livers (Fig 4.7 A).…”

“…Ifi27l2b encodes a hydrophobic protein that is located on the inner mitochondrial membrane and overexpression of Ifi27l2b has led to mitochondrial membrane depolarisation, release of cytochrome C and subsequent mitochondria mediated apoptosis (215). Increased expression of Ifi27l2b has been observed in response to stimulation with IFNα and a toll like receptor stimulant (poly I:C) and overexpression has led to caspase-dependent cell death (215). The human equivalent of this gene IFI27 was found strongly induced by IFNα and poly I:C, and had 3-17 fold higher expression in primary human keratinocytes on treatment with TNFα, IFNγ and TGFβ1 (227,228).…”

Endothelial Cell Sensitization by Death Receptor Fractions of an Anti–Dengue Nonstructural Protein 1 Antibody Induced Plasma Leakage, Coagulopathy, and Mortality in Mice

“…Rather than autoantibody-induced cell death, several studies have focused on the apoptosis that is directly induced by DENV infections (52)(53)(54). Studies have demonstrated that DENV infections elicit proapoptotic responses involving the suppression of Bcl-2 and Bcl-x L as well as the induction of Bax (40)(41)(42). The induction of TRAIL has been reported in human endothelial-like ECV304 cells following DENV infection (55).…”

“…Additionally, Bcl-2 family members, Bax and Bcl-x L , which previous studies have shown to be involved in the DENV-mediated regulation of cell death (40)(41)(42)(43), were analyzed for comparison. RT-PCR analysis revealed that the mRNA expression levels of the proapoptotic TRAIL-R1 (DR4) and Bax were upregulated after subcytotoxic DENV challenge (Supplemental Fig.…”