Interferon signaling suppresses the unfolded protein response and induces cell death in hepatocytes accumulating hepatitis B surface antigen

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.

Network analysis of hepatocellular carcinoma liquid biopsies augmented by single-cell sequencing data

“…Two cfRNA modules also showed preservation only in hepatocytes and one of the modules was enriched for pathways participating in fatty acid metabolism-a well described characteristic of hepatocytes ( Alhazzaa et al, 2013 ; Alves-Bezerra and Cohen, 2017 ). While the other module was enriched for pathways indicating cellular stress and perhaps pointing towards viral infection, in particular with the hepatitis-B virus ( Seo et al, 2018 ; Li et al, 2019 ; Baudi et al, 2021 )—a known contributor to the development of hepatocellular carcinoma ( Maucort-Boulch et al, 2018 ). Lipid metabolism and particularly fatty acid metabolism dysregulation is a well described characteristic of different cancers, including HCC ( Fernández et al, 2020 ; Hu et al, 2020 ).…”

The Immune Pathogenesis of Acute-On-Chronic Liver Failure and the Danger Hypothesis

“…Baudi et al. found that acute liver injury induced by IFN-α-mediated virus infection could be alleviated by inhibiting GRP78 through a mechanism that involves IFN-α induction of ER stress-related cell death by reducing the unfolded protein response (UPR), with GRP78 promoting high UPR expression and reducing IFN-α-mediated liver injury in mice ( 74 ). Zhang et al.…”

“…However, some studies have reported that GRP78 and GRP94 are important factors for acute liver injury or liver failure. Baudi et al found that acute liver injury induced by IFN-a-mediated virus infection could be alleviated by inhibiting GRP78 through a mechanism that involves IFN-a induction of ER stress-related cell death by reducing the unfolded protein response (UPR), with GRP78 promoting high UPR expression and reducing IFN-amediated liver injury in mice (74). Zhang et al found that peroxisome proliferator-activated receptor a (PPARa) can improve liver injury caused by ALF; the mechanism is mainly to reduce hepatocyte apoptosis by regulating endoplasmic reticulum stress and reducing the expression of GRP78, GRP94, and other proteins (75).…”

Are Humanized Mouse Models Useful for Basic Research of Hepatocarcinogenesis through Chronic Hepatitis B Virus Infection?

“…In contrast, ER stress in hepatocytes is also induced by the accumulation of large HB proteins [90,91]. When HB proteins accumulate in the ER, the ER expands and releases Ca 2+ into the cytoplasm, activating ER stress signaling [88,90,91,97].…”