| 18 | 0 | 223 |
| 下载次数 | 被引频次 | 阅读次数 |
黄病毒属病毒是危害全球公共卫生的单股正链RNA病毒,当前仍缺少广谱高效的疫苗与抗病毒药物,防控形势严峻。RNA甲基化作为表观转录调控的关键方式,在黄病毒感染过程中发挥重要调控作用。本文系统总结了黄病毒属病毒RNA甲基化的研究进展,从两个核心层面进行阐述:一是病毒基因组自身的甲基化修饰,包括5′UTR帽子修饰、开放阅读框及3′UTR区域修饰,通过调控病毒RNA的稳定性、翻译、复制与免疫逃逸直接影响感染进程;二是病毒感染引发宿主RNA甲基化重编程,通过改变宿主关键基因的甲基化水平,干扰免疫应答与细胞代谢,间接为病毒复制创造有利条件。文章同时梳理了相关检测技术发展与研究争议,表明RNA甲基化具有明显的位点特异性与病毒特异性。最后展望了靶向甲基化通路的抗病毒药物、减毒疫苗及诊断标志物的开发前景,为黄病毒防控提供新的理论支撑与研究方向。
Abstract:Flaviviruses are single-stranded positive-sense RNA viruses that pose a significant threat to global public health. The lack of broad-spectrum and highly effective vaccines and antiviral drugs presents a considerable challenge for the prevention and control of these viruses. RNA methylation, a critical mechanism of epitranscriptional regulation, plays an important regulatory role during flavivirus infection. This review systematically summarizes the research progress on flavivirus RNA methylation in two core perspectives. First, the methylation modifications of the viral genome, including modifications of the 5′ UTR cap, the open reading frame, and the 3′ UTR. These modifications directly influence the infection process by regulating viral RNA stability, translation, replication, and immune evasion. Second, the reprogramming of host RNA methylation induced by viral infection. By altering the methylation levels of key host genes, this process disrupts immune responses and cellular metabolism, indirectly creating a favorable environment for viral replication. This article also reviews the development of related detection technologies and current research controversies, highlighting the significant site-specificity and virus-specific nature of RNA methylation. Finally, we discuss the potential for developing antiviral drugs, attenuated vaccines, and diagnostic markers targeting methylation pathways, offering new theoretical support and research directions for prevention and control of flavivirus infection.
[1]Kramer LD, Li J, Shi PY. West Nile virus[J]. Lancet Neurol, 2007, 6(2):171-181. DOI:10. 1016/S1474-4422(07)70030-3.
[2]Paz-Bailey G, Adams LE, Deen J, et al. Dengue[J].Lancet, 2024, 403(10427):667-682. DOI:10. 1016/s0140-6736(23)02576-x.
[3]Simmonds P, Becher P, Bukh J, et al. ICTV virus taxonomy profile:Flaviviridae[J]. J Gen Virol, 2017,98(1):2-3. DOI:10. 1099/jgv. 0. 000672.
[4]Chambers TJ, Hahn CS, Galler R, et al. Flavivirus genome organization, expression, and replication[J].Annu Rev Microbiol, 1990, 44:649-688. DOI:10. 1146/annurev. mi. 44. 100190. 003245.
[5]Liu L, Dong H, Chen H, et al. Flavivirus RNA cap methyltransferase:structure, function, and inhibition[J]. Front Biol, 2010, 5(4):286-303. DOI:10. 1007/s11515-010-0660-y.
[6]Leyssen P, De Clercq E, Neyts J. Perspectives for the treatment of infections with Flaviviridae[J]. Clin Microbiol Rev, 2000, 13(1):67-82. DOI:10. 1128/cmr. 13. 1. 67.
[7]吴芳,成文召,赵飞媛,等. m6A修饰在人类相关致病病毒中的作用与研究进展[J].病毒学报,2019, 35(5):813-821. DOI:10. 13242/j. cnki.bingduxuebao. 003593.
[8]郝好杰,余宝成,胡章立,等. RNA修饰在病毒复制中的功能[J].病毒学报,2022, 38(6):1519-1536.DOI:10. 13242/j. cnki. bingduxuebao. 220182.
[9]Zhang Y, Zhang LS, Dai Q, et al. 5-methylcytosine(m5C)RNA modification controls the innate immune response to virus infection by regulating type I interferons[J]. Proc Natl Acad Sci U S A, 2022, 119(42):e2123338119. DOI:10. 1073/pnas. 2123338119.
[10]Baquero-Pérez B, Yonchev ID, Delgado-Tejedor A, et al. N6-methyladenosine modification is not a general trait of viral RNA genomes[J]. Nat Commun, 2024,15:1964. DOI:10. 1038/s41467-024-46278-9.
[11]Gokhale NS, McIntyre ABR, McFadden MJ, et al. N6-methyladenosine in Flaviviridae viral RNA genomes regulates infection[J]. Cell Host Microbe, 2016, 20(5):654-665. DOI:10. 1016/j. chom. 2016. 09. 015.
[12]Li Y, Jin H, Li Q, et al. The role of RNA methylation in tumor immunity and its potential in immunotherapy[J]. Mol Cancer, 2024, 23(1):130. DOI:10. 1186/s12943-024-02041-8.
[13]Cui L, Ma R, Cai J, et al. RNA modifications:importance in immune cell biology and related diseases[J]. Signal Transduct Target Ther, 2022, 7:334.DOI:10. 1038/s41392-022-01175-9.
[14]Liu Y, Li K, Xu YP, et al. Characterization of m6A modifications in the contemporary Zika virus genome and host cellular transcripts[J]. J Med Virol, 2022, 94(9):4309-4318. DOI:10. 1002/jmv. 27869.
[15]Li M, Tao Z, Zhao Y, et al. 5-methylcytosine RNA methyltransferases and their potential roles in cancer[J].J Transl Med, 2022, 20(1):214. DOI:10. 1186/s12967-022-03427-2.
[16]Luo Y, Yao Y, Wu P, et al. The potential role of N7-methylguanosine(m7G)in cancer[J]. J Hematol Oncol, 2022, 15(1):63. DOI:10. 1186/s13045-022-01285-5.
[17]Yoon KJ. Voyages to map unexplored parts of the epitranscriptomic world[J]. Exp Mol Med, 2022, 54(10):1599-1600. DOI:10. 1038/s12276-022-00825-w.
[18]Li Z, Lao Y, Yan R, et al. N6-methyladenosine(m6A)modification in inflammation:a bibliometric analysis and literature review[J]. PeerJ, 2024:12:e18645. DOI:10. 7717/peerj. 18645.
[19]Lin X, Ke X, Jian X, et al. Azacytidine targeting SARS-CoV-2 viral RNA as a potential treatment for COVID-19[J]. Sci Bull, 2022, 67(10):1022-1025. DOI:10. 1016/j. scib. 2022. 02. 002.
[20]Barbieri I, Kouzarides T. Role of RNA modifications in cancer[J]. Nat Rev Cancer, 2020, 20(6):303-322.DOI:10. 1038/s41568-020-0253-2.
[21]Zaccara S, Ries RJ, Jaffrey SR. Reading, writing and erasing mRNA methylation[J]. Nat Rev Mol Cell Biol,2019, 20(10):608-624. DOI:10. 1038/s41580-019-0168-5.
[22]Daffis S, Szretter KJ, Schriewer J, et al. 2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members[J]. Nature, 2010,468(7322):452-456. DOI:10. 1038/nature09489.
[23]Ray D, Shah A, Tilgner M, et al. West Nile virus 5′-cap structure is formed by sequential guanine N-7 and ribose 2′-O methylations by nonstructural protein 5[J].J Virol, 2006, 80(17):8362-8370. DOI:10. 1128/jvi. 00814-06.
[24]Devarkar SC, Wang C, Miller MT, et al. Structural basis for m7G recognition and 2′-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I[J]. Proc Natl Acad Sci U S A, 2016,113(3):596-601. DOI:10. 1073/pnas. 1515152113.
[25]Li SH, Dong H, Li XF, et al. Rational design of a flavivirus vaccine by abolishing viral RNA 2′-OMethylation[J]. J Virol, 2013, 87(10):5812-5819.DOI:10. 1128/jvi. 02806-12.
[26]Hyde JL, Gardner CL, Kimura T, et al. A viral RNA structural element alters host recognition of nonself RNA[J]. Science, 2014, 343(6172):783-787. DOI:10. 1126/science. 1248465.
[27]Kumar P, Sweeney TR, Skabkin MA, et al. Inhibition of translation by IFIT family members is determined by their ability to interact selectively with the 5′-terminal regions of cap0-,cap1-and 5′ppp-mRNAs[J]. Nucleic Acids Res, 2014, 42(5):3228-3245. DOI:10. 1093/nar/gkt1321.
[28]Vom Hemdt A, Thienel AL, Ciupka K, et al. 2′-Omethyltransferase-deficient yellow fever virus:Restricted replication in the midgut and secondary tissues of Aedes aegypti mosquitoes severely limits dissemination[J]. PLoS Pathog, 2024, 20(10):e1012607. DOI:10. 1371/journal. ppat. 1012607.
[29]Wu X, Zhang Y, Wang M, et al. Methyltransferasedeficient avian flaviviruses are attenuated due to suppression of viral RNA translation and induction of a higher innate immunity[J]. Front Immunol, 2021, 12:751688. DOI:10. 3389/fimmu. 2021. 751688.
[30]Züst R, Cervantes-Barragan L, Habjan M, et al.Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5[J]. Nat Immunol, 2011, 12(2):137-143. DOI:10. 1038/ni. 1979.
[31]Schuberth-Wagner C, Ludwig J, Bruder AK, et al. A conserved histidine in the RNA sensor RIG-I controls immune tolerance to N1-2′O-methylated self RNA[J].Immunity, 2015, 43(1):41-51. DOI:10. 1016/j.immuni. 2015. 06. 015.
[32]Han SR, Lee SW. Inhibition of Japanese encephalitis virus(JEV)replication by specific RNA aptamer against JEV methyltransferase[J]. Biochem Biophys Res Commun, 2017, 483(1):687-693. DOI:10. 1016/j.bbrc. 2016. 12. 081.
[33]Chang DC, Hoang LT, Mohamed Naim AN, et al.Evasion of early innate immune response by 2′-Omethylation of dengue genomic RNA[J]. Virology,2016, 499:259-266. DOI:10. 1016/j.virol. 2016. 09. 022.
[34]Gokhale NS, McIntyre ABR, Mattocks MD, et al.Altered m6A modification of specific cellular transcripts affects Flaviviridae infection[J]. Mol Cell, 2020, 77(3):542-555. e8. DOI:10. 1016/j.molcel. 2019. 11. 007.
[35]Ren W, Fu C, Zhang Y, et al. Zika virus NS5 protein inhibits type I interferon signaling via CRL3 E3 ubiquitin ligase-mediated degradation of STAT2[J]. Proc Natl Acad Sci U S A, 2024, 121(34):e2403235121. DOI:10. 1073/pnas. 2403235121.
[36]Ruggieri A, Helm M, Chatel-Chaix L. An epigenetic′extreme makeover′:the methylation of flaviviral RNA(and beyond)[J]. RNA Biol, 2021, 18(5):696-708.DOI:10. 1080/15476286. 2020. 1868150.
[37]Lichinchi G, Zhao BS, Wu Y, et al. Dynamics of human and viral RNA methylation during zika virus infection[J]. Cell Host Microbe, 2016, 20(5):666-673. DOI:10. 1016/j. chom. 2016. 10. 002.
[38]Yao M, Cheng Z, Li X, et al. N6-methyladenosine modification positively regulate Japanese encephalitis virus replication[J]. Virol J, 2024, 21(1):23. DOI:10. 1186/s12985-023-02275-w.
[39]Malbec L, Zhang T, Chen YS, et al. Dynamic methylome of internal mRNA N7-methylguanosine and its regulatory role in translation[J]. Cell Res, 2019, 29(11):927-941. DOI:10. 1038/s41422-019-0230-z.
[40]Zhang LS, Liu C, Ma H, et al. Transcriptome-wide mapping of internal N7-methylguanosine methylome in mammalian mRNA[J]. Mol Cell, 2019, 74(6):1304-1316. e8. DOI:10. 1016/j. molcel. 2019. 03. 036.
[41]Wang X, Zhang Y, Chen K, et al. m7GHub V2. 0:an updated database for decoding the N7-methylguanosine(m7G)epitranscriptome[J]. Nucleic Acids Res, 2024,52(D1):D203-D212. DOI:10. 1093/nar/gkad789.
[42]Lu L, Zheng J, Liu B, et al. The m7G modification level and immune infiltration characteristics in patients with COVID-19[J]. J Multidiscip Healthc, 2022, 15:2461-2472. DOI:10. 2147/JMDH. S385050.
[43]Pandolfini L, Barbieri I, Bannister AJ, et al. METTL1Promotes let-7 microRNA Processing via m7G Methylation[J]. Mol Cell, 2019, 74(6):1278-1290.e9. DOI:10. 1016/j. molcel. 2019. 03. 040.
[44]Ma J, Zheng S, An C, et al. Pathogenic mechanism and therapeutic intervention of impaired N7-methylguanosine(m7G)tRNA modification[J]. Proc Natl Acad Sci U S A, 2024, 121(45):e2405886121.DOI:10. 1073/pnas. 2405886121.
[45]Villordo SM, Filomatori CV, Sánchez-Vargas I, et al.Dengue virus RNA structure specialization facilitates host adaptation[J]. PLoS Pathog, 2015, 11(1):e1004604. DOI:10. 1371/journal. ppat. 1004604.
[46]Li XH, Chen J, Ou YD, et al. m6A modification associated with YTHDF1 is involved in Japanese encephalitis virus infection[J]. Vet Microbiol, 2023,287:109887. DOI:10. 1016/j. vetmic. 2023. 109887.
[47]Kim GW, Siddiqui A. N6-methyladenosine modification of HCV RNA genome regulates capindependent IRES-mediated translation via YTHDC2recognition[J]. Proc Natl Acad Sci U S A, 2021, 118(10):e2022024118. DOI:10. 1073/pnas. 2022024118.
[48]Wang H, Feng J, Zeng C, et al. NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infections[J]. Emerg Microbes Infect, 2023, 12(1):2178238.DOI:10. 1080/22221751. 2023. 2178238.
[49]Denolly S, Stukalov A, Barayeu U, et al. Zika virus remodelled ER membranes contain proviral factors involved in redox and methylation pathways[J]. Nat Commun, 2023, 14:8045. DOI:10. 1038/s41467-023-43665-6.
[50]Moon JS, Siddiqui A, Kim GW. Regulation of viral hepatitis by N6-methyladenosine RNA methylation[J].Emerg Microbes Infect, 2025, 14(1):2544726. DOI:10. 1080/22221751. 2025. 2544726.
[51]Zhang JN, et al. RNA m6A dynamic modification mediated by nucleus-localized FTO is involved in follicular reserve[J]. Zool Res, 2024, 45(2):415-428.DOI:10. 24272/j. issn. 2095-8137. 2023. 236.
[52]Chen J, Zhong LH, Chen JX, et al. Flaviviridae RdRp exploits NSUN2-driven m5C methylation to establish persistent infection[J]. PLoS Pathog, 2025, 21(12):e1013765. DOI:10. 1371/journal. ppat. 1013765.
[53]Liu J, Xu YP, Li K, et al. The m6A methylome of SARS-CoV-2 in host cells[J]. Cell Res, 2021, 31(4):404-414. DOI:10. 1038/s41422-020-00465-7.
[54]Wang H, Feng J, Fu Z, et al. Epitranscriptomic m5C methylation of SARS-CoV-2 RNA regulates viral replication and the virulence of progeny viruses in the new infection[J]. Sci Adv, 2024, 10(32):eadn9519.DOI:10. 1126/sciadv. adn9519.
[55]Li ZL, Xie Y, Wang Y, et al. NSUN2-mediated HCV RNA m5C methylation facilitates viral RNA stability and replication[J]. Genom Proteom Bioinform, 2025,23:qzaf008. DOI:10. 1093/gpbjnl/qzaf008.
[56]Ahmed-Belkacem R, Sutto-Ortiz P, Guiraud M, et al.Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase[J]. Eur J Med Chem,2020, 201:112557. DOI:10. 1016/j.ejmech. 2020. 112557.
[57]Li Y, Wang Y, Zhang Z, et al. Genome-wide detection of high abundance N6-methyladenosine sites by microarray[J]. Rna, 2015, 21(8):1511-1518. DOI:10. 1261/rna. 051474. 115.
[58]Chen K, Lu Z, Wang X, et al. High-resolution N6-methyladenosine(m6A)map using photo-crosslinkingassisted m6A sequencing[J]. Angew Chem Int Ed,2015, 54(5):1587-1590. DOI:10. 1002/anie. 201410647.
[59]Liu N, Parisien M, Dai Q, et al. Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA[J]. Rna, 2013, 19(12):1848-1856. DOI:10. 1261/rna. 041178. 113.
[60]Garcia-Campos MA, Edelheit S, Toth U, et al.Deciphering the“m6A code” via antibody-independent quantitative profiling[J]. Cell, 2019, 178(3):731-747.e16. DOI:10. 1016/j. cell. 2019. 06. 013.
[61]Leitner M, Murigneux V, Etebari K, et al. Wolbachia elevates host methyltransferase expression and alters the m6A methylation landscape in Aedes aegypti mosquito cells[J]. BMC Microbiol, 2025, 25(1):164. DOI:10. 1186/s12866-025-03898-5.
[62]Wilson C, Chen PJ, Miao Z, et al. Programmable m6A modification of cellular RNAs with a Cas13-directed methyltransferase[J]. Nat Biotechnol, 2020, 38(12):1431-1440. DOI:10. 1038/s41587-020-0572-6.
[63]Li M, Song N, Sun D, et al. Transcriptome mapping of the internal N7-methylguanosine methylome in messenger RNAs in human oral squamous cell carcinoma[J]. Front Biosci(Landmark Ed), 2023, 28(12):330. DOI:10. 31083/j. fbl2812330.
[64]Shu X, Cao J, Cheng M, et al. A metabolic labeling method detects m6A transcriptome-wide at single base resolution[J]. Nat Chem Biol, 2020, 16(8):887-895.DOI:10. 1038/s41589-020-0526-9.
[65]Wang Y, Zhao Y, Bollas A, et al. Nanopore sequencing technology, bioinformatics and applications[J]. Nat Biotechnol, 2021, 39(11):1348-1365. DOI:10. 1038/s41587-021-01108-x.
[66]Meyer KD. DART-seq:an antibody-free method for global m6A detection[J]. Nat Meth, 2019, 16(12):1275-1280. DOI:10. 1038/s41592-019-0570-0.
[67]Dai Q, Ye C, Irkliyenko I, et al. Ultrafast bisulfite sequencing detection of 5-methylcytosine in DNA and RNA[J]. Nat Biotechnol, 2024, 42(10):1559-1570.DOI:10. 1038/s41587-023-02034-w.
[68]Paranjape SM, Harris E. Y box-binding protein-1 binds to the dengue virus 3′-untranslated region and mediates antiviral effects[J]. J Biol Chem, 2007, 282(42):30497-30508. DOI:10. 1074/jbc. M705755200.
[69]Diosa-Toro M, Kennedy DR, Chuo V, et al. Y-box binding protein 1 interacts with dengue virus nucleocapsid and mediates viral assembly[J]. mBio,2022, 13:e00196-e00122. DOI:10. 1128/mbio. 00196-22.
[70]Samrat SK, Bashir Q, Huang Y, et al. Broad-spectrum small-molecule inhibitors targeting the SAM-binding site of flavivirus NS5 methyltransferase[J]. ACS Infect Dis, 2023, 9(7):1319-1333.
[71]Lim SP, Sonntag LS, Noble C, et al. Small molecule inhibitors that selectively block dengue virus methyltransferase[J]. J Biol Chem, 2011, 286(8):6233-6240. DOI:10. 1074/jbc. m110. 179184.
[72]Song W, Zhang H, Zhang Y, et al. Identification and characterization of zika virus NS5 methyltransferase inhibitors[J]. Front Cell Infect Microbiol, 2021, 11:665379. DOI:10. 3389/fcimb. 2021. 665379.
[73]Moser JC, Papadopoulos KP, Rodon Ahnert J, et al.Phase 1 dose escalation and cohort expansion study evaluating safety, PK, PD and clinical activity of STC-15, a METTL-3 inhibitor, in patients with advanced malignancies[J]. J Clin Oncol, 2024, 42(16_suppl):2586. DOI:10. 1200/jco. 2024. 42. 16_suppl. 2586.
[74]Züst R, Dong H, Li XF, et al. Rational design of a live attenuated dengue vaccine:2′-O-methyltransferase mutants are highly attenuated and immunogenic in mice and macaques[J]. PLoS Pathog, 2013, 9(8):e1003521. DOI:10. 1371/journal. ppat. 1003521.
[75]Verbeke R, Hogan MJ, LoréK, et al. Innate immune mechanisms of mRNA vaccines[J]. Immunity, 2022,55(11):1993-2005. DOI:10. 1016/j.immuni. 2022. 10. 014.
[76]Qing X, Chen Q, Wang K. m6A regulator-mediated methylation modification patterns and characteristics in COVID-19 patients[J]. Front Public Health, 2022,10:914193. DOI:10. 3389/fpubh. 2022. 914193.
[77]Zhang R, Xia Y, Dong J, et al. Comprehensive analysis of m7G-related genes and chronic hepatitis B:diagnostic markers, immune microenvironment regulation, disease progression[J]. J Immunol Res,2023, 2023(1):9471520. DOI:10. 1155/2023/9471520.
[78]Han X, Xu C, Song Y, et al. The role of m6A regulators mRNA expression in peripheral blood mononuclear cells in chronic hepatitis B:a novel diagnostic and prognostic indicator[J]. BMC Gastroenterol, 2025, 25(1):464. DOI:10. 1186/s12876-025-04067-8.
基本信息:
中图分类号:R373
引用信息:
[1]黄锦弟,唐瑞霞,杜廷福.黄病毒-宿主互作中的表观转录组调控:RNA甲基化修饰的功能与机制[J].病毒学报().
2026-09-08
2026-09-08
2026-09-08