A Long Noncoding RNA Regulates Hepatitis C Virus Infection Through Interferon Alpha-Inducible Protein 6

Overview

Journal Hepatology

Specialty Gastroenterology

Date 2018 Sep 11

PMID 30199576

Citations 40

Authors

Xiao Liu

Xiaoqiong Duan

Jacinta A Holmes

Wenting Li

Sae Hwan Lee

Zeng Tu

Chuanlong Zhu

Shadi Salloum

Anna Lidofsky

Esperance A Schaefer

Dachuan Cai

Shilin Li

Haoju Wang

Yongfu Huang

Yongju Zhao

Ming-Lung Yu

Zhiwen Xu

Limin Chen

Jian Hong

Wenyu Lin

Raymond T Chung

Affiliations

Soon will be listed here.

Abstract

Long noncoding RNAs (lncRNAs) play a critical role in the regulation of many important cellular processes. However, the mechanisms by which lncRNAs regulate viral infection and host immune responses are not well understood. We sought to explore lncRNA regulation of hepatitis C virus (HCV) infection and interferon response. We performed RNA sequencing (RNAseq) in Huh7.5.1 cells with or without interferon alpha (IFNα) treatment. Clustered regularly interspaced short palindromic repeats/Cas9 guide RNA (gRNA) was used to knock out selected genes. The promoter clones were constructed, and the activity of related interferon-stimulated genes (ISGs) were detected by the secrete-pair dual luminescence assay. We constructed the full-length and four deletion mutants of an interferon-induced lncRNA RP11-288L9.4 (lncRNA-IFI6) based on predicted secondary structure. Selected gene mRNAs and their proteins, together with HCV infection, in Huh7.5.1 cells and primary human hepatocytes (PHHs) were monitored by quantitative real-time PCR (qRT-PCR) and western blot. We obtained 7,901 lncRNAs from RNAseq. A total of 1,062 host-encoded lncRNAs were significantly differentially regulated by IFNα treatment. We found that lncRNA-IFI6 gRNA significantly inhibited HCV infection compared with negative gRNA control. The expression of the antiviral ISG IFI6 was significantly increased following lncRNA-IFI6 gRNA editing compared with negative gRNA control in Japanese fulminant hepatitis 1 (JFH1)-infected Huh7.5.1 cells and PHHs. We observed that lncRNA-IFI6 regulation of HCV was independent of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling. lncRNA-IFI6 negatively regulated IFI6 promoter function through histone modification. Overexpression of the truncated spatial domain or full-length lncRNA-IFI6 inhibited IFI6 expression and increased HCV replication. Conclusion: A lncRNA, lncRNA-IFI6, regulates antiviral innate immunity in the JFH1 HCV infection model. lncRNA-IFI6 regulates HCV infection independently of the JAK-STAT pathway. lncRNA-IFI6 exerts its regulatory function via promoter activation and histone modification of IFI6 through its spatial domain.

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References

de Veer M, Holko M, Frevel M, Walker E, Der S, Paranjape J . Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol. 2001; 69(6):912-20. View

Fried M, Shiffman M, Reddy K, Smith C, Marinos G, Goncales Jr F . Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002; 347(13):975-82. DOI: 10.1056/NEJMoa020047. View

Hadziyannis S, Sette Jr H, Morgan T, Balan V, Diago M, Marcellin P . Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004; 140(5):346-55. DOI: 10.7326/0003-4819-140-5-200403020-00010. View

Lin W, Choe W, Hiasa Y, Kamegaya Y, Blackard J, Schmidt E . Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology. 2005; 128(4):1034-41. DOI: 10.1053/j.gastro.2005.02.006. View

Itsui Y, Sakamoto N, Kurosaki M, Kanazawa N, Tanabe Y, Koyama T . Expressional screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication. J Viral Hepat. 2006; 13(10):690-700. DOI: 10.1111/j.1365-2893.2006.00732.x. View

Randall G, Chen L, Panis M, Fischer A, Lindenbach B, Sun J . Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection. Gastroenterology. 2006; 131(5):1584-91. DOI: 10.1053/j.gastro.2006.08.043. View

Tai A, Chung R . Treatment failure in hepatitis C: mechanisms of non-response. J Hepatol. 2008; 50(2):412-20. PMC: 2743341. DOI: 10.1016/j.jhep.2008.11.010. View

Itsui Y, Sakamoto N, Kakinuma S, Nakagawa M, Sekine-Osajima Y, Tasaka-Fujita M . Antiviral effects of the interferon-induced protein guanylate binding protein 1 and its interaction with the hepatitis C virus NS5B protein. Hepatology. 2009; 50(6):1727-37. DOI: 10.1002/hep.23195. View

Chen L, Sun J, Meng L, Heathcote J, Edwards A, McGilvray I . ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment. J Gen Virol. 2009; 91(Pt 2):382-8. DOI: 10.1099/vir.0.015388-0. View

10.

Lin W, Tsai W, Shao R, Wu G, Peng L, Barlow L . Hepatitis C virus regulates transforming growth factor beta1 production through the generation of reactive oxygen species in a nuclear factor kappaB-dependent manner. Gastroenterology. 2010; 138(7):2509-18, 2518.e1. PMC: 2883661. DOI: 10.1053/j.gastro.2010.03.008. View

11.

Gupta R, Shah N, Wang K, Kim J, Horlings H, Wong D . Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010; 464(7291):1071-6. PMC: 3049919. DOI: 10.1038/nature08975. View

12.

Amaral P, Clark M, Gascoigne D, Dinger M, Mattick J . lncRNAdb: a reference database for long noncoding RNAs. Nucleic Acids Res. 2010; 39(Database issue):D146-51. PMC: 3013714. DOI: 10.1093/nar/gkq1138. View

13.

Nagano T, Fraser P . No-nonsense functions for long noncoding RNAs. Cell. 2011; 145(2):178-81. DOI: 10.1016/j.cell.2011.03.014. View

14.

Chen L, Li S, McGilvray I . The ISG15/USP18 ubiquitin-like pathway (ISGylation system) in hepatitis C virus infection and resistance to interferon therapy. Int J Biochem Cell Biol. 2011; 43(10):1427-31. DOI: 10.1016/j.biocel.2011.06.006. View

15.

Wang K, Chang H . Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011; 43(6):904-14. PMC: 3199020. DOI: 10.1016/j.molcel.2011.08.018. View

16.

Arnaud N, Dabo S, Akazawa D, Fukasawa M, Shinkai-Ouchi F, Hugon J . Hepatitis C virus reveals a novel early control in acute immune response. PLoS Pathog. 2011; 7(10):e1002289. PMC: 3192838. DOI: 10.1371/journal.ppat.1002289. View

17.

Mohammad F, Pandey G, Mondal T, Enroth S, Redrup L, Gyllensten U . Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing. Development. 2012; 139(15):2792-803. DOI: 10.1242/dev.079566. View

18.

Li K, Lemon S . Innate immune responses in hepatitis C virus infection. Semin Immunopathol. 2012; 35(1):53-72. PMC: 3732459. DOI: 10.1007/s00281-012-0332-x. View

19.

Yang J, Li J, Jiang S, Zhou H, Qu L . ChIPBase: a database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from ChIP-Seq data. Nucleic Acids Res. 2012; 41(Database issue):D177-87. PMC: 3531181. DOI: 10.1093/nar/gks1060. View

20.

Mercer T, Mattick J . Structure and function of long noncoding RNAs in epigenetic regulation. Nat Struct Mol Biol. 2013; 20(3):300-7. DOI: 10.1038/nsmb.2480. View