Abstract
Virus infection, such as hepatitis B virus (HBV), occasionally causes endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is counteractive machinery to ER stress, and the failure of UPR to cope with ER stress results in cell death. Mechanisms that regulate the balance between ER stress and UPR are poorly understood. Type 1 and type 2 interferons have been implicated in hepatic flares during chronic HBV infection. Here, we examined the interplay between ER stress, UPR, and IFNs using transgenic mice that express hepatitis B surface antigen (HBsAg) (HBs-Tg mice) and humanized-liver chimeric mice infected with HBV. IFNα causes severe and moderate liver injury in HBs-Tg mice and HBV infected chimeric mice, respectively. The degree of liver injury is directly correlated with HBsAg levels in the liver, and reduction of HBsAg in the transgenic mice alleviates IFNα mediated liver injury. Analyses of total gene expression and UPR biomarkers’ protein expression in the liver revealed that UPR is induced in HBs-Tg mice and HBV infected chimeric mice, indicating that HBsAg accumulation causes ER stress. Notably, IFNα administration transiently suppressed UPR biomarkers before liver injury without affecting intrahepatic HBsAg levels. Furthermore, UPR upregulation by glucose-regulated protein 78 (GRP78) suppression or low dose tunicamycin alleviated IFNα mediated liver injury. These results suggest that IFNα induces ER stress-associated cell death by reducing UPR. IFNγ uses the same mechanism to exert cytotoxicity to HBsAg accumulating hepatocytes. Collectively, our data reveal a previously unknown mechanism of IFN-mediated cell death. This study also identifies UPR as a potential target for regulating ER stress-associated cell death.
Highlights
Interferons (IFNs) play a critical role in host defense against pathogens, viruses, by activating the expression of hundreds of genes that exert antiviral activity [1]
We demonstrate that IFN-1s cause severe and moderate hepatitis in transgenic mice expressing hepatitis B surface antigen (HBs-Tg mice) and human hepatocyte chimeric mice infected with Hepatitis B virus (HBV), respectively
Our results indicate that IFN-1s suppress unfolded protein response (UPR) before causing liver injury
Summary
Interferons (IFNs) play a critical role in host defense against pathogens, viruses, by activating the expression of hundreds of genes that exert antiviral activity [1]. IFNs cause immunopathology during viral infections [2,3]. Little is known about whether and how infected cells are preferentially sensitized to IFN-mediated cell death. To cope with ER stress, a protective mechanism called the unfolded protein response (UPR) is activated to reduce protein synthesis and/or enhance degradation, folding, and secretion of the offending proteins [4,5]. While unmitigated ER stress leads to cell death [12], it is unclear whether the concomitant UPR plays a proor anti-cell survival role in such cases. Infections with several viruses have been reported to induce ER stress [14,15,16,17,18,19], the interplay between ER stress, UPR, and IFN signaling has not been adequately interrogated
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