Role of hepcidin upregulation and proteolytic cleavage of ferroportin 1 in hepatitis C virus-induced iron accumulation.

IF 6.7 1区 医学 Q1 Immunology and Microbiology
PLoS Pathogens Pub Date : 2023-08-16 eCollection Date: 2023-08-01 DOI:10.1371/journal.ppat.1011591
Kazuyoshi Ohta, Masahiko Ito, Takeshi Chida, Kenji Nakashima, Satoshi Sakai, Yumi Kanegae, Hideya Kawasaki, Takuya Aoshima, Shuji Takabayashi, Hirotaka Takahashi, Kazuhito Kawata, Ikuo Shoji, Tatsuya Sawasaki, Takafumi Suda, Tetsuro Suzuki
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引用次数: 0

Abstract

Hepatitis C virus (HCV) is a pathogen characterized not only by its persistent infection leading to the development of cirrhosis and hepatocellular carcinoma (HCC), but also by metabolic disorders such as lipid and iron dysregulation. Elevated iron load is commonly observed in the livers of patients with chronic hepatitis C, and hepatic iron overload is a highly profibrogenic and carcinogenic factor that increases the risk of HCC. However, the underlying mechanisms of elevated iron accumulation in HCV-infected livers remain to be fully elucidated. Here, we observed iron accumulation in cells and liver tissues under HCV infection and in mice expressing viral proteins from recombinant adenoviruses. We established two molecular mechanisms that contribute to increased iron load in cells caused by HCV infection. One is the transcriptional induction of hepcidin, the key hormone for modulating iron homeostasis. The transcription factor cAMP-responsive element-binding protein hepatocyte specific (CREBH), which was activated by HCV infection, not only directly recognizes the hepcidin promoter but also induces bone morphogenetic protein 6 (BMP6) expression, resulting in an activated BMP-SMAD pathway that enhances hepcidin promoter activity. The other is post-translational regulation of the iron-exporting membrane protein ferroportin 1 (FPN1), which is cleaved between residues Cys284 and Ala285 in the intracytoplasmic loop region of the central portion mediated by HCV NS3-4A serine protease. We propose that host transcriptional activation triggered by endoplasmic reticulum stress and FPN1 cleavage by viral protease work in concert to impair iron efflux, leading to iron accumulation in HCV-infected cells.

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铁调素上调和ferroportin 1蛋白水解裂解在丙型肝炎病毒诱导的铁积聚中的作用。
丙型肝炎病毒(HCV)是一种病原体,其特征不仅是其持续感染导致肝硬化和肝细胞癌(HCC)的发展,而且还表现为代谢紊乱,如脂质和铁失调。慢性丙型肝炎患者的肝脏中通常观察到铁负荷升高,而肝脏铁负荷是一种高度促纤维化和致癌因素,会增加HCC的风险。然而,丙型肝炎病毒感染的肝脏中铁积聚增加的潜在机制仍有待完全阐明。在这里,我们观察到在HCV感染下细胞和肝组织中以及在表达重组腺病毒的病毒蛋白的小鼠中铁的积累。我们建立了两种分子机制,它们有助于HCV感染引起的细胞铁负荷增加。一种是铁调素的转录诱导,铁调素是调节铁稳态的关键激素。丙型肝炎病毒感染激活的转录因子cAMP反应元件结合蛋白肝细胞特异性(CREBH)不仅直接识别铁调素启动子,而且诱导骨形态发生蛋白6(BMP6)的表达,导致激活的BMP-SMAD途径增强铁调素启动子的活性。另一种是铁输出膜蛋白ferroportin 1(FPN1)的翻译后调节,其在HCV NS3-4A丝氨酸蛋白酶介导的中心部分细胞质内环区的残基Cys284和Ala285之间裂解。我们提出,内质网应激触发的宿主转录激活和病毒蛋白酶切割FPN1协同作用,损害铁的流出,导致HCV感染细胞中的铁积累。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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