Induction of Selenoprotein P mRNA during Hepatitis C Virus Infection Inhibits RIG-I-Mediated Antiviral Immunity
Induction of Selenoprotein P mRNA during Hepatitis C Virus Infection Inhibits RIG-I-Mediated Antiviral Immunity
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DOI：
10.1016/j.chom.2019.02.015
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发表时间：
2019-04-10
影响因子：
30.3
通讯作者：
Kaneko, Shuichi
中科院分区：
文献类型：
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作者：
Murai, Kazuhisa;Honda, Masao;Kaneko, Shuichi
感染丙型肝炎病毒(丙型肝炎病毒)的患者患2型糖尿病的风险增加。丙型肝炎病毒感染与各种肝脏异常有关，可能导致这种联系。我们发现，丙型肝炎病毒感染增加了肝脏硒蛋白P(SEP)mRNA(SEP1mRNA)和血清SEP水平，这是一种与胰岛素抵抗有关的肝细胞因子。SEPP1通过限制病毒RNA感受器维甲酸诱导基因I(RIG-I)的功能来抑制I型干扰素反应。SEPP1mRNA直接与RIG-I结合并抑制其活性。肝细胞中SEPP1基因的敲除导致干扰素刺激基因的强烈诱导，并减少丙型肝炎病毒的复制。临床上，在丙型肝炎病毒感染的患者中，高SEP水平与直接作用的抗病毒药物治疗失败显著相关。因此，SEP调节胰岛素抵抗和先天免疫，可能诱导肝脏的免疫耐受，其上调可能解释了丙型肝炎病毒感染患者患2型糖尿病风险增加的原因。
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.