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

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 s...

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Published inPLoS pathogens Vol. 17; no. 5; p. e1009228
Main Authors Baudi, Ian, Isogawa, Masanori, Moalli, Federica, Onishi, Masaya, Kawashima, Keigo, Ishida, Yuji, Tateno, Chise, Sato, Yusuke, Harashima, Hideyoshi, Ito, Hiroyasu, Ishikawa, Tetsuya, Wakita, Takaji, Iannacone, Matteo, Tanaka, Yasuhito
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 12.05.2021
Public Library of Science (PLoS)
Subjects
Accumulation
Antibodies
Antigens
Apoptosis
Biology and Life Sciences
Care and treatment
Cell death
Cellular signal transduction
Cluster analysis
Development and progression
DNA microarrays
Engineering and Technology
Genetic aspects
Health aspects
Hepatitis
Hepatitis associated antigen
Hepatitis B
Hepatitis B surface antigen
Hepatocytes
Injuries
Interferon
Liver
Medicine and Health Sciences
Nitric oxide
Nitric-oxide synthase
Phosphorylation
Protein folding
Protein synthesis
Proteins
Research and Analysis Methods
Ribonuclease L
Rodents
Salt
Signaling
Viral infections
α-Interferon
Japan
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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.
AbstractList 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. Hepatitis B virus (HBV) causes acute and chronic infections that kill over 600,000 people every year from severe hepatitis, liver cirrhosis, and cancer. Mechanisms of chronic liver injury remain largely unknown. Both type 1 and type 2 interferons (IFNs) have been implicated in hepatic flares during chronic HBV infection, although HBV per se is a poor IFN inducer. For example, high serum IFNα levels have been observed in chronic hepatitis B patients experiencing a spontaneous or treatment-associated exacerbation of liver damage. These clinical observations suggest a pathogenic role of IFNs in HBV infection. Here, 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 HBV, respectively. HBsAg accumulation appears to cause ER stress because a counteractive response to ER stress, namely, unfolded protein response (UPR), was induced in both HBs-Tg mice and HBV infected chimeric mice. Our results indicate that IFN-1s suppress UPR before causing liver injury. UPR was also suppressed by IFNγ. Induction of UPR in HBs-Tg mice before treatment with IFNα and IFNγ significantly alleviated liver injury. We suggest that IFNs exert cytotoxicity to ER stress accumulating cells by suppressing UPR.
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.
The basis behind the IFN-mediated immunopathology has yet to be fully elucidated but appears to include phosphorylation of eukaryotic initiation factor-2α (eIF-2α), activation of RNase L, and induction of nitric oxide synthase (iNOS) [1,2]. Patients with chronic hepatitis B (CHB) often experience hepatic flares in association with hepatitis B surface antigen (HBsAg) accumulation [20,21]. (C) The percentage of TUNEL positive area in WT and HBs-Tg mice after IFNα treatment (*** Dunn’s post hoc test, p<0.0001). https://doi.org/10.1371/journal.ppat.1009228.g002 Next, we examined whether the reduction of intracellular HBsAg levels correlates with the severity of IFN-1 mediated liver injury in HBs-Tg mice. Representative immunoblots showing HBsAg and ISG15 levels on days 0, 1, and 15. https://doi.org/10.1371/journal.ppat.1009228.g003 IFN-1 signaling perturbs UPR in association with liver injury in HBs-Tg mice To elucidate the molecular mechanism by which IFN-1 induces liver injury in HBs-Tg mice, we serially profiled the liver transcriptomes of both HBs-Tg and control mice treated with IFNα by microarray analyses.
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. IFN[alpha] 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 IFN[alpha] 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, IFN[alpha] 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 IFN[alpha] mediated liver injury. These results suggest that IFN[alpha] induces ER stress-associated cell death by reducing UPR. IFN[gamma] 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.
The basis behind the IFN-mediated immunopathology has yet to be fully elucidated but appears to include phosphorylation of eukaryotic initiation factor-2α (eIF-2α), activation of RNase L, and induction of nitric oxide synthase (iNOS) [1,2]. Patients with chronic hepatitis B (CHB) often experience hepatic flares in association with hepatitis B surface antigen (HBsAg) accumulation [20,21]. (C) The percentage of TUNEL positive area in WT and HBs-Tg mice after IFNα treatment (*** Dunn’s post hoc test, p<0.0001). https://doi.org/10.1371/journal.ppat.1009228.g002 Next, we examined whether the reduction of intracellular HBsAg levels correlates with the severity of IFN-1 mediated liver injury in HBs-Tg mice. Representative immunoblots showing HBsAg and ISG15 levels on days 0, 1, and 15. https://doi.org/10.1371/journal.ppat.1009228.g003 IFN-1 signaling perturbs UPR in association with liver injury in HBs-Tg mice To elucidate the molecular mechanism by which IFN-1 induces liver injury in HBs-Tg mice, we serially profiled the liver transcriptomes of both HBs-Tg and control mice treated with IFNα by microarray analyses.
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.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.
Audience Academic
Author Ishikawa, Tetsuya
Sato, Yusuke
Moalli, Federica
Onishi, Masaya
Tateno, Chise
Wakita, Takaji
Ito, Hiroyasu
Isogawa, Masanori
Ishida, Yuji
Harashima, Hideyoshi
Baudi, Ian
Iannacone, Matteo
Tanaka, Yasuhito
Kawashima, Keigo
AuthorAffiliation 5 Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan
Albany Medical College, UNITED STATES
10 Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
4 Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
1 Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
12 Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
8 Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
6 Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
7 PhoenixBio Co., Ltd., Higashi-Hiroshima, Japan
9 Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University School of Medicine, Toyoake, Japan
11 National Institute of Inf
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/33979382$$D View this record in MEDLINE/PubMed
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2021 Baudi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2021 Baudi et al 2021 Baudi et al
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– notice: 2021 Baudi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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SSID ssj0041316
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Snippet Virus infection, such as hepatitis B virus (HBV), occasionally causes endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is counteractive...
The basis behind the IFN-mediated immunopathology has yet to be fully elucidated but appears to include phosphorylation of eukaryotic initiation factor-2α...
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SourceType Open Website
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StartPage e1009228
SubjectTerms Accumulation
Antibodies
Antigens
Apoptosis
Biology and Life Sciences
Care and treatment
Cell death
Cellular signal transduction
Cluster analysis
Development and progression
DNA microarrays
Engineering and Technology
Genetic aspects
Health aspects
Hepatitis
Hepatitis associated antigen
Hepatitis B
Hepatitis B surface antigen
Hepatocytes
Injuries
Interferon
Liver
Medicine and Health Sciences
Nitric oxide
Nitric-oxide synthase
Phosphorylation
Protein folding
Protein synthesis
Proteins
Research and Analysis Methods
Ribonuclease L
Rodents
Salt
Signaling
Viral infections
α-Interferon
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Title Interferon signaling suppresses the unfolded protein response and induces cell death in hepatocytes accumulating hepatitis B surface antigen
URI https://www.ncbi.nlm.nih.gov/pubmed/33979382
https://www.proquest.com/docview/2541853660
https://www.proquest.com/docview/2526302239
https://pubmed.ncbi.nlm.nih.gov/PMC8143404
https://doaj.org/article/e016bc46b1164d8e848ca52ceee39270
http://dx.doi.org/10.1371/journal.ppat.1009228
Volume 17
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