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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\u03b1 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\u03b1 mediated liver injury. Analyses of total gene expression and UPR biomarkers\u2019 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\u03b1 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\u03b1 mediated liver injury. These results suggest that IFN\u03b1 induces ER stress-associated cell death by reducing UPR. IFN\u03b3 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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009228","type":"journal-article","created":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T13:54:11Z","timestamp":1620827651000},"page":"e1009228","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Interferon signaling suppresses the unfolded protein response and induces cell death in hepatocytes accumulating hepatitis B surface antigen"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8645-1571","authenticated-orcid":true,"given":"Ian","family":"Baudi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8730-4303","authenticated-orcid":true,"given":"Masanori","family":"Isogawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Moalli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaya","family":"Onishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0985-1111","authenticated-orcid":true,"given":"Keigo","family":"Kawashima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Ishida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chise","family":"Tateno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0913-7815","authenticated-orcid":true,"given":"Yusuke","family":"Sato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideyoshi","family":"Harashima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4836-4001","authenticated-orcid":true,"given":"Hiroyasu","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8506-4948","authenticated-orcid":true,"given":"Tetsuya","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaji","family":"Wakita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9370-2671","authenticated-orcid":true,"given":"Matteo","family":"Iannacone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2473-6966","authenticated-orcid":true,"given":"Yasuhito","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,5,12]]},"reference":[{"key":"ppat.1009228.ref001","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1128\/CMR.14.4.778-809.2001","article-title":"Antiviral Actions of Interferons","volume":"14","author":"CE Samuel","year":"2001","journal-title":"Clin Microbiol Rev"},{"key":"ppat.1009228.ref002","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/nri3787","article-title":"Type I interferons in infectious disease","volume":"15","author":"F McNab","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"ppat.1009228.ref003","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.immuni.2006.08.007","article-title":"Type I Interferons in Host Defense","volume":"25","author":"DB Stetson","year":"2006","journal-title":"Immunity"},{"key":"ppat.1009228.ref004","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nrm2199","article-title":"Signal integration in the endoplasmic reticulum unfolded protein response","volume":"8","author":"D Ron","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ppat.1009228.ref005","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nrm3270","article-title":"The unfolded protein response: controlling cell fate decisions under ER stress and beyond","volume":"13","author":"C. 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