DOI QR코드

DOI QR Code

The Significance of N6-Methyladenosine RNA Methylation in Regulating the Hepatitis B Virus Life Cycle

  • Jae-Su Moon (Division of Infectious Diseases, Department of Medicine, University of California) ;
  • Wooseong Lee (Center for Convergent Research of Emerging virus Infection, Korea Research Institute of Chemical Technology (KRICT)) ;
  • Yong-Hee Cho (Data Convergence Drug Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT)) ;
  • Yonghyo Kim (Data Convergence Drug Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT)) ;
  • Geon-Woo Kim (Department of Microbiology and Molecular Biology, Chungnam National University)
  • 투고 : 2023.09.08
  • 심사 : 2023.10.23
  • 발행 : 2024.02.28

초록

N6-methyladenosine (m6A) RNA methylation has recently emerged as a significant co-transcriptional modification involved in regulating various RNA functions. It plays a vital function in numerous biological processes. Enzymes referred to as m6A methyltransferases, such as the methyltransferase-like (METTL) 3-METTL14-Wilms tumor 1 (WT1)-associated protein (WTAP) complex, are responsible for adding m6A modifications, while m6A demethylases, including fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5), can remove m6A methylation. The functions of m6A-methylated RNA are regulated through the recognition and interaction of m6A reader proteins. Recent research has shown that m6A methylation takes place at multiple sites within hepatitis B virus (HBV) RNAs, and the location of these modifications can differentially impact the HBV infection. The addition of m6A modifications to HBV RNA can influence its stability and translation, thereby affecting viral replication and pathogenesis. Furthermore, HBV infection can also alter the m6A modification pattern of host RNA, indicating the virus's ability to manipulate host cellular processes, including m6A modification. This manipulation aids in establishing chronic infection, promoting liver disease, and contributing to pathogenesis. A comprehensive understanding of the functional roles of m6A modification during HBV infection is crucial for developing innovative approaches to combat HBV-mediated liver disease. In this review, we explore the functions of m6A modification in HBV replication and its impact on the development of liver disease.

키워드

과제정보

This work was supported by research fund of Chungnam National University.

참고문헌

  1. Seeger C, Mason WS. 2015. Molecular biology of hepatitis B virus infection. Virology 479-480: 672-686. https://doi.org/10.1016/j.virol.2015.02.031
  2. Hu J, Protzer U, Siddiqui A. 2019. Revisiting Hepatitis B Virus: challenges of curative therapies. J. Virol. 93: e01032-19.
  3. Yan H, Zhong GC, Xu GW, He WH, Jing ZY, Gao ZC, et al. 2012. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 1: e00049.
  4. Iwamoto M, Saso W, Sugiyama R, Ishii K, Ohki M, Nagamori S, et al. 2019. Epidermal growth factor receptor is a host-entry cofactor triggering hepatitis B virus internalization. Proc. Natl. Acad. Sci. USA 116: 8487-8492. https://doi.org/10.1073/pnas.1811064116
  5. Seeger C, Mason WS. 2000. Hepatitis B virus biology. Microbiol. Mol. Biol. Rev. 64: 51-68. https://doi.org/10.1128/MMBR.64.1.51-68.2000
  6. Roundtree IA, Evans ME, Pan T, He C. 2017. Dynamic RNA modifications in gene expression regulation. Cell 169: 1187-1200. https://doi.org/10.1016/j.cell.2017.05.045
  7. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, et al. 2012. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485: 201-206. https://doi.org/10.1038/nature11112
  8. Yue Y, Liu J, He C. 2015. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 29: 1343-1355. https://doi.org/10.1101/gad.262766.115
  9. Wang X, Feng J, Xue Y, Guan ZY, Zhang DL, Liu Z, et al. 2017. Structural basis of N6-adenosine methylation by the METTL3- METTL14 complex (vol 534, pg 575, 2016). Nature 542: 260-260.
  10. Fu Y, Jia GF, Pang XQ, Wang RN, Wang X, Li CJ, et al. 2013. FTO-mediated formation of N-6-hydroxymethyladenosine and N-6- formyladenosine in mammalian RNA. Nat. Commun. 4: 1798.
  11. Zheng GQ, Dahl JA, Niu YM, Fedorcsak P, Huang CM, Li CJ, et al. 2013. ALKBH5 is a mammalian RNA demethylase that Impacts RNA metabolism and mouse fertility. Mol. Cell 49: 18-29. https://doi.org/10.1016/j.molcel.2012.10.015
  12. Patil DP, Pickering BF, Jaffrey SR. 2018. Reading m(6)A in the transcriptome: m(6)A-binding proteins. Trends Cell Biol. 28: 113-127. https://doi.org/10.1016/j.tcb.2017.10.001
  13. Shi HL, Wang X, Lu ZK, Zhao BXS, Ma HH, Hsu PJ, et al. 2017. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res. 27: 315-328. https://doi.org/10.1038/cr.2017.15
  14. Wang X, Zhao BS, Roundtree IA, Lu ZK, Han DL, Ma HH, et al. 2015. N-6-methyladenosine modulates messenger RNA translation efficiency. Cell 161: 1388-1399. https://doi.org/10.1016/j.cell.2015.05.014
  15. Du H, Zhao Y, He JQ, Zhang Y, Xi HR, Liu MF, et al. 2016. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat. Commun. 7: 12626.
  16. Xiao W, Adhikari S, Dahal U, Chen YS, Hao YJ, Sun BF, et al. 2016. Nuclear m(6)A reader YTHDC1 regulates mRNA splicing. Mol. Cell 61: 507-519. https://doi.org/10.1016/j.molcel.2016.01.012
  17. Kretschmer J, Rao H, Hackert P, Sloan KE, Hobartner C, Bohnsack MT. 2018. The m(6)A reader protein YTHDC2 interacts with the small ribosomal subunit and the 5'-3' exoribonuclease XRN1. RNA 24: 1339-1350. https://doi.org/10.1261/rna.064238.117
  18. Mao YH, Dong LM, Liu XM, Guo JY, Ma HH, Shen B, et al. 2019. m(6)A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2. Nat. Commun. 10: 5332.
  19. Kim GW, Siddiqui A. 2021. The role of N6-methyladenosine modification in the life cycle and disease pathogenesis of hepatitis B and C viruses. Exp. Mol. Med. 53: 339-345. https://doi.org/10.1038/s12276-021-00581-3
  20. Imam H, Kim GW, Siddiqui A. 2020. Epitranscriptomic(N6-methyladenosine) modification of viral RNA and virus-host interactions. Front. Cell. Infect. Microbiol. 10: 584283.
  21. Gonzales-van Horn SR, Sarnow P. 2017. Making the Mark: The role of adenosine modifications in the life cycle of RNA viruses. Cell Host Microbe 21: 661-669. https://doi.org/10.1016/j.chom.2017.05.008
  22. Courtney DG, Tsai K, Bogerd HP, Kennedy EM, Law BA, Emery A, et al. 2019. Epitranscriptomic addition of m(5)C to HIV-1 transcripts regulates viral gene expression. Cell Host Microbe 26: 217-227 e216.
  23. Gokhale NS, McIntyre ABR, McFadden MJ, Roder AE, Kennedy EM, Gandara JA, et al. 2016. N6-methyladenosine in flaviviridae viral RNA genomes regulates infection. Cell Host Microbe 20: 654-665. https://doi.org/10.1016/j.chom.2016.09.015
  24. Kennedy EM, Bogerd HP, Kornepati AV, Kang D, Ghoshal D, Marshall JB, et al. 2016. Posttranscriptional m(6)A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe 19: 675-685. https://doi.org/10.1016/j.chom.2016.04.002
  25. Tan B, Gao SJ. 2018. The RNA epitranscriptome of DNA viruses. J. Virol. 92: e00696-18.
  26. Kane SE, Beemon K. 1985. Precise localization of m6A in Rous sarcoma virus RNA reveals clustering of methylation sites: implications for RNA processing. Mol. Cell. Biol. 5: 2298-2306. https://doi.org/10.1128/MCB.5.9.2298
  27. Hesser CR, Karijolich J, Dominissini D, He C, Glaunsinger BA. 2018. N6-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi's sarcoma-associated herpesvirus infection. PLoS Pathog. 14: e1006995.
  28. Kim GW, Moon JS, Gudima SO, Siddiqui A. 2022. N6-methyladenine modification of hepatitis delta virus regulates its virion assembly by recruiting YTHDF1. J. Virol. 96: e0112422.
  29. Imam H, Khan M, Gokhale NS, McIntyre ABR, Kim GW, Jang JY, et al. 2018. N6-methyladenosine modification of hepatitis B virus RNA differentially regulates the viral life cycle. Proc. Natl. Acad. Sci. USA 115: 8829-8834. https://doi.org/10.1073/pnas.1808319115
  30. Kim GW, Moon JS, Siddiqui A. 2022. N6-methyladenosine modification of the 5' epsilon structure of the HBV pregenome RNA regulates its encapsidation by the viral core protein. Proc. Natl. Acad. Sci. USA 119: e2120485119.
  31. Kim GW, Imam H, Siddiqui A. 2021. The RNA binding proteins YTHDC1 and FMRP regulate the nuclear export of N6 - methyladenosine-modified Hepatitis B virus transcripts and affect the viral life cycle. J. Virol. 95: e0009721.
  32. Kim GW, Siddiqui A. 2022. Hepatitis B virus X protein expression is tightly regulated by N6-methyladenosine modification of its mRNA. J. Virol. 96: e0165521.
  33. Imam H, Kim GW, Mir SA, Khan M, Siddiqui A. 2020. Interferon-stimulated gene 20 (ISG20) selectively degrades N6- methyladenosine modified Hepatitis B Virus transcripts. PLoS Pathog. 16: e1008338.
  34. Kim GW, Siddiqui A. 2021. Hepatitis B virus X protein recruits methyltransferases to affect cotranscriptional N6-methyladenosine modification of viral/host RNAs. Proc. Natl. Acad. Sci. USA 118: e201945118.
  35. Zheng YY, Chen WL, Louie SG, Yen TSB, Ou JHJ. 2007. Hepatitis B virus promotes hepatocarcinogenesis in transgenic mice. Hepatology 45: 16-21. https://doi.org/10.1002/hep.21445
  36. Kariko K, Buckstein M, Ni H, Weissman D. 2005. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23: 165-175. https://doi.org/10.1016/j.immuni.2005.06.008
  37. Durbin AF, Wang C, Marcotrigiano J, Gehrke L. 2016. RNAs Containing modified nucleotides fail to trigger RIG-I conformational changes for innate immune signaling. mBio 7: e00833-16.
  38. Sioud M, Furset G, Cekaite L. 2007. Suppression of immunostimulatory siRNA-driven innate immune activation by 2'-modified RNAs. Biochem. Biophys. Res. Commun. 361: 122-126. https://doi.org/10.1016/j.bbrc.2007.06.177
  39. Uzri D, Gehrke L. 2009. Nucleotide sequences and modifications that determine RIG-I/RNA binding and signaling activities. J. Virol. 83: 4174-4184. https://doi.org/10.1128/JVI.02449-08
  40. Takeuchi O, Akira S. 2009. Innate immunity to virus infection. Immunol. Rev. 227: 75-86. https://doi.org/10.1111/j.1600-065X.2008.00737.x
  41. Schlee M, Hartmann G. 2016. Discriminating self from non-self in nucleic acid sensing. Nat. Rev. Immunol. 16: 566-580. https://doi.org/10.1038/nri.2016.78
  42. Sato S, Li K, Kameyama T, Hayashi T, Ishida Y, Murakami S, et al. 2015. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for Hepatitis B virus. Immunity 42: 123-132. https://doi.org/10.1016/j.immuni.2014.12.016
  43. Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M, Jr. 2008. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454: 523-527. https://doi.org/10.1038/nature07106
  44. Khan M, Syed GH, Kim SJ, Siddiqui A. 2016. Hepatitis B virus-induced Parkin-dependent recruitment of Linear Ubiquitin Assembly Complex (LUBAC) to mitochondria and attenuation of innate immunity. PLoS Pathog. 12: e1005693.
  45. Kim GW, Imam H, Khan M, Siddiqui A. 2020. N6-Methyladenosine modification of hepatitis B and C viral RNAs attenuates host innate immunity via RIG-I signaling. J. Biol. Chem. 295: 13123-13133. https://doi.org/10.1074/jbc.RA120.014260
  46. Li N, Hui H, Bray B, Gonzalez GM, Zeller M, Anderson KG, et al. 2021. METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection. Cell Rep. 35: 109091.
  47. Lu M, Zhang Z, Xue M, Zhao BS, Harder O, Li A, et al. 2020. N6 -methyladenosine modification enables viral RNA to escape recognition by RNA sensor RIG-I. Nat. Microbiol. 5: 584-598. https://doi.org/10.1038/s41564-019-0653-9
  48. Kim GW, Imam H, Khan M, Mir SA, Kim SJ, Yoon SK, et al. 2020. HBV-induced increased N6-methyladenosine modification of PTEN RNA affects innate immunity and contributes to HCC. Hepatology 73: 533-547. https://doi.org/10.1016/j.jhep.2020.02.030
  49. Chen CY, Chen J, He L, Stiles BL. 2018. PTEN: Tumor suppressor and metabolic regulator. Front. Endocrinol. (Lausanne) 9: 338.
  50. Li S, Zhu M, Pan R, Fang T, Cao YY, Chen S, et al. 2016. The tumor suppressor PTEN has a critical role in antiviral innate immunity. Nat. Immunol. 17: 241-249. https://doi.org/10.1038/ni.3311
  51. Zhao T, Qi J, Liu T, Wu H, Zhu Q. 2022. N6-methyladenosine modification participates in the progression of Hepatitis B virus-related liver fibrosis by regulating immune cell infiltration. Front. Med. (Lausanne) 9: 821710.
  52. Rao X, Lai L, Li X, Wang L, Li A, Yang Q. 2021. N6 -methyladenosine modification of circular RNA circ-ARL3 facilitates Hepatitis B virus-associated hepatocellular carcinoma via sponging miR-1305. IUBMB Life 73: 408-417. https://doi.org/10.1002/iub.2438
  53. Song MS, Salmena L, Pandolfi PP. 2012. The functions and regulation of the PTEN tumour suppressor. Nat. Rev. Mol. Cell Biol. 13: 283-296. https://doi.org/10.1038/nrm3330
  54. Wang C, Yang W, Yan HX, Luo T, Zhang J, Tang L, et al. 2012. Hepatitis B virus X (HBx) induces tumorigenicity of hepatic progenitor cells in 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated HBx transgenic mice. Hepatology 55: 108-120. https://doi.org/10.1002/hep.24675
  55. Tirumuru N, Zhao BS, Lu W, Lu Z, He C, Wu L. 2016. N(6)-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. Elife 5: e15528.
  56. Lichinchi G, Zhao BS, Wu Y, Lu Z, Qin Y, He C, et al. 2016. Dynamics of human and viral RNA methylation during Zika virus infection. Cell Host Microbe 20: 666-673. https://doi.org/10.1016/j.chom.2016.10.002
  57. Guo G, Pan K, Fang S, Ye L, Tong X, Wang Z, et al. 2021. Advances in mRNA 5-methylcytosine modifications: Detection, effectors, biological functions, and clinical relevance. Mol. Ther. Nucleic Acids 26: 575-593. https://doi.org/10.1016/j.omtn.2021.08.020
  58. Dimitrova DG, Teysset L, Carre C. 2019. RNA 2'-O-methylation (Nm) modification in human diseases. Genes (Basel) 10: 117.