Induction of Selenoprotein P mRNA during Hepatitis C Virus Infection Inhibits RIG-I-Mediated Antiviral Immunity

• Published in: Cell host & microbe Vol. 25; no. 4; pp. 588 - 601.e7
• Main Authors: Murai, Kazuhisa, Honda, Masao, Shirasaki, Takayoshi, Shimakami, Tetsuro, Omura, Hitoshi, Misu, Hirofumi, Kita, Yuki, Takeshita, Yumie, Ishii, Kiyo-aki, Takamura, Toshinari, Urabe, Takeshi, Shimizu, Ryogo, Okada, Hikari, Yamashita, Taro, Sakai, Yoshio, Kaneko, Shuichi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.04.2019
• Subjects: chronic hepatitis C; DEAD Box Protein 58 - antagonists & inhibitors; direct-acting antiviral drugs; Hepatitis C - pathology; hepatitis C virus; hepatokine; Host-Pathogen Interactions; Humans; Immune Evasion; innate immunity; interferon; Receptors, Immunologic; retinoic-acid-inducible gene I; RNA, Messenger - metabolism; selenoprotein P; Selenoprotein P - biosynthesis; type 2 diabetes; type 2 diabetes; innate immunity; chronic hepatitis C; hepatokine; hepatitis C virus; retinoic-acid-inducible gene I; interferon; direct-acting antiviral drugs; selenoprotein P
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2019.02.015

Patients infected with hepatitis C virus (HCV) have an increased risk of developing type 2 diabetes. HCV infection is linked to various liver abnormalities, potentially contributing to this association. We show that HCV infection increases the levels of hepatic selenoprotein P (SeP) mRNA (SEPP1 mRNA) and serum SeP, a hepatokine linked to insulin resistance. SEPP1 mRNA inhibits type I interferon responses by limiting the function of retinoic-acid-inducible gene I (RIG-I), a sensor of viral RNA. SEPP1 mRNA binds directly to RIG-I and inhibits its activity. SEPP1 mRNA knockdown in hepatocytes causes a robust induction of interferon-stimulated genes and decreases HCV replication. Clinically, high SeP serum levels are significantly associated with treatment failure of direct-acting antivirals in HCV-infected patients. Thus, SeP regulates insulin resistance and innate immunity, possibly inducing immune tolerance in the liver, and its upregulation may explain the increased risk of type 2 diabetes in HCV-infected patients. [Display omitted] •SeP, a hepatokine causing insulin resistance, is increased in HCV patients•SeP mRNA binds to RIG-I and inhibits RIG-I-mediated type I IFN immune responses•The full-length structure of SEPP1 mRNA is required to regulate RIG-I activity•Increased serum SeP in chronic hepatitis C patients is associated with DAAs failure RIG-I initiates immune responses against most RNA viruses. Murai et al. reveal that mRNA encoding selenoprotein P (SeP), a hepatokine causing insulin resistance and type 2 diabetes, binds and inhibits RIG-I activity. SeP is induced upon hepatitis C virus infection and is associated with treatment failure of direct-acting antiviral drugs.