AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Genes & Diseases Article
PDF (3.3 MB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Full Length Article | Open Access

Targeting m6A modification inhibits herpes virus 1 infection

Zhuoying Fenga, Fanghang Zhoua, Miaomiao Tana, Tingting Wanga, Ying Chena, Wenwen Xub, Bin Lib, Xin Wanga( ), Xin Denga( ), Ming-Liang Hea,c( )
Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, PR China
MOE Key Laboratory of Tumor Molecular Biology and Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, PR China
CityU Shenzhen Research Institute, Shenzhen, Guangdong 518057, PR China

Peer review under responsibility of Chongqing Medical University.

Show Author Information

Abstract

The latent infection by herpes virus type 1 (HSV-1) may be lifelong in trigeminal ganglia and a suspected cause of Alzheimer's Disease (AD) and Amyotrophic lateral sclerosis (ALS). Whether and how N6-methyladenosine (m6A) modification of viral RNAs affects virus infection are poorly understood. Here, we report that HSV-1 infection enhanced the expression of m6A writers (METTL3, METTL14) and readers (YTHDF1/2/3) at the early infection stage and decreased their expression later on, while suppressed the erasers' (FTO, ALBKH5) expression immediately upon infection to facilitate viral replication. Inhibiting m6A modification by 3-deazaadenosine (DAA) significantly decreased viral replication and reduced viral reproduction over 1000 folds. More interestingly, depleting the writers and readers by siRNAs inhibited virus replication and reproduction; whereas depleting the erasers promoted viral replication and reproduction. Silencing YTHDF3 strikingly decreased viral replication by up to 90%, leading to reduction of up to 10-fold viral replication and over 100-fold virus reproduction, respectively. Depletion of m6A initiator METTL3 (by 60%–70%) by siRNA correlatedly decreased viral replication 60%–70%, and reduced virus yield over 30-fold. Consistently, ectopic expression of METTL3 largely increased virus yield. METTL3 knockdown suppressed the HSV-1 intermediate early and early genes (ICP0, ICP8 and UL23) and late genes (VP16, UL44, UL49 and ICP47); while ectopic expression of METTL3 upregulated these gene expression. Results from our study shed the lights on the importance for m6A modification to initiate HSV-1 early replication. The components of m6A modification machinery, particularly m6A initiator METTL3 and reader YTHDF3, would be potential important targets for combating HSV-1 infections.

Keywords

Gene silencingHSV-1 infectionm6A modificationVirus replicationVirus reproduction

References

1

Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Nat Acad Sci U S A. 1974;71(10):3971-3975.
Crossref Google Scholar
2

Wei CM, Gershowitz A, Moss B. Methylated nucleotides block 5′ terminus of HeLa cell messenger RNA. Cell. 1975;4(4):379-386.
Crossref Google Scholar
3

Wei CM, Moss B. Nucleotide sequences at the N6-methyladenosine sites of HeLa cell messenger ribonucleic acid. Biochemistry. 1977;16(8):1672-1676.
Crossref Google Scholar
4

Wang X, Lu Z, Gomez A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505(7481):117-120.
Crossref Google Scholar
5

Wei W, Ji X, Guo X, Ji S. Regulatory role of N 6 -methyladenosine (m 6 A) methylation in RNA processing and human diseases. J Cell Biochem. 2017;118(9):2534-2543.
Crossref Google Scholar
6

Wei CM, Gershowitz A, Moss B. 5′-Terminal and internal methylated nucleotide sequences in HeLa cell mRNA. Biochemistry. 1976;15(2):397-401.
Crossref Google Scholar
7

Batista PJ, Molinie B, Wang J, et al. m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell. 2014;15(6):707-719.
Crossref Google Scholar
8

Dominissini D, Moshitch-Moshkovitz S, Schwartz S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485(7397):201-206.
Crossref Google Scholar
9

Huang J, Yin P. Structural insights into N6-methyladenosine (m6A) modification in the transcriptome. Genomics Proteomics Bioinformatics. 2018;16(2):85-89.
Crossref Google Scholar
10

Wang X, Huang J, Zou T, Yin P. Human m(6)A writers: two subunits, 2 roles. RNA Biol. 2017;14(3):300-304.
Crossref Google Scholar
11

Zhang C, Fu J, Zhou Y. A review in research progress concerning m6A methylation and immunoregulation. Front Immunol. 2019;10:922.
Crossref Google Scholar
12

Wang X, Zhao BS, Roundtree IA, et al. N6-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161(6):1388-1399.
Crossref Google Scholar
13

Roignant JY, Soller M. m6A in mRNA: an ancient mechanism for fine-tuning gene expression. Trends Genet. 2017;33(6):380-390.
Crossref Google Scholar
14

Shi H, Wang X, Lu Z, et al. YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res. 2017;27(3):315-328.
Crossref Google Scholar
15

Zheng G, Dahl JA, Niu Y, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49(1):18-29.
Crossref Google Scholar
16

Jia G, Fu Y, Zhao X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7(12):885-887.
Crossref Google Scholar
17

Fu Y, Jia G, Pang X, et al. FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA. Nat Commun. 2013;4:1798.
Crossref Google Scholar
18

Batista PJ, Molinie B, Wang J, et al. m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell. 2014;15(6):707-719.
Crossref Google Scholar
19

Widagdo J, Anggono V. The m6A-epitranscriptomic signature in neurobiology: from neurodevelopment to brain plasticity. J Neurochem. 2018;147(2):137-152.
Crossref Google Scholar
20

Chen J, Fang X, Zhong P, Song Z, Hu X. N6-methyladenosine modifications: interactions with novel RNA-binding proteins and roles in signal transduction. RNA Biol. 2019;16(8):991-1000.
Crossref Google Scholar
21

Wu DF, Koch T, Liang YJ, et al. Membrane glycoprotein M6a interacts with the micro-opioid receptor and facilitates receptor endocytosis and recycling. J Biol Chem. 2007;282(30):22239-22247.
Crossref Google Scholar
22

Sekar D, Lakshmanan G. Methylation of N6-adenosine (m6A) modification in miRNAs and its implications in immunity. Epigenomics. 2020;12(13):1083-1085.
Crossref Google Scholar
23

Han M, Liu Z, Xu Y, et al. Abnormality of m6A mRNA methylation is involved in Alzheimer’s disease. Front Neurosci. 2020;14:98.
Crossref Google Scholar
24

Wang S, Sun C, Li J, et al. Roles of RNA methylation by means of N(6)-methyladenosine (m(6)A) in human cancers. Cancer Lett. 2017;408:112-120.
Crossref Google Scholar
25

Brocard M, Ruggieri A, Locker N. m6A RNA methylation, a new hallmark in virus-host interactions. J Gen Virol. 2017;98(9):2207-2214.
Crossref Google Scholar
26

McGeoch DJ, Rixon FJ, Davison AJ. Topics in herpesvirus genomics and evolution. Virus Res. 2006;117(1):90-104.
Crossref Google Scholar
27

Amin I, Vajeeha A, Younas S, et al. HSV-1 infection: role of viral proteins and cellular receptors. Crit Rev Eukaryot Gene Expr. 2019;29(5):461-469.
Crossref Google Scholar
28

Wan Q, Song D, Li H, He ML. Stress proteins: the biological functions in virus infection, present and challenges for target-based antiviral drug development. Sign Transduct Target Ther. 2020;5(1):125.
Crossref Google Scholar
29

Danastas K, Miranda-Saksena M, Cunningham AL. Herpes simplex virus type 1 interactions with the interferon system. Int J Mol Sci. 2020;21(14):5150.
Crossref Google Scholar
30

Dimock K, Stoltzfus CM. Sequence specificity of internal methylation in B77 avian sarcoma virus RNA subunits. Biochemistry. 1977;16(3):471-478.
Crossref Google Scholar
31

Hashimoto SI, Green M. Multiple methylated cap sequences in adenovirus type 2 early mRNA. J Virol. 1976;20(2):425-435.
Crossref Google Scholar
32

Kim GW, Imam H, Khan M, Siddiqui A. N6-Methyladenosine modification of hepatitis B and C viral RNAs attenuates host innate immunity via RIG-I signaling. J Biol Chem. 2020;295(37):13123-13133.
Crossref Google Scholar
33

Zhou F, Wan Q, Lu J, Chen Y, Lu G, He ML. Pim1 impacts enterovirus A71 replication and represents a potential target in antiviral therapy. iScience. 2019;19:715-727.
Crossref Google Scholar
34

Schremser V, Antoniewicz L, Tschachler E, Geusau A. Polymerase chain reaction for the diagnosis of herpesvirus infections in dermatology : analysis of clinical data. Wien Klin Wochenschr. 2020;132(1-2):35-41.
Crossref Google Scholar
35

Dan X, Wan Q, Yi L, et al. Hsp27 responds to and facilitates enterovirus A71 replication by enhancing viral internal ribosome entry site-mediated translation. J Virol. 2019;93(9):e02322–18.
Crossref Google Scholar
36

Dominissini D, Moshitch-Moshkovitz S, Salmon-Divon M, Amariglio N, Rechavi G. Transcriptome-wide mapping of N(6)-methyladenosine by m(6)A-seq based on immunocapturing and massively parallel sequencing. Nat Protoc. 2013;8(1):176-189.
Crossref Google Scholar
37

Meng J, Lu Z, Liu H, et al. A protocol for RNA methylation differential analysis with MeRIP-Seq data and exomePeak R/Bioconductor package. Methods. 2014;69(3):274-281.
Crossref Google Scholar
38

Imam H, Khan M, Gokhale NS. N6-methyladenosine modification of hepatitis B virus RNA differentially regulates the viral life cycle. Proc Nat Acad Sci U S A. 2018;115(35):8829-8834.
Crossref Google Scholar
39

Gokhale NS, Mclntyre ABR, McFadden MJ, et al. N6-Methyladenosine in flaviviridae viral RNA genomes regulates infection. Cell Host Microbe. 2016;20(5):654-665.
Crossref Google Scholar
40

de Clercq E, Montgomery JA. Broad-spectrum antiviral activity of the carbocyclic analog of 3-deazaadenosine. Antivir Res. 1983;3(1):17-24.
Crossref Google Scholar
41

Montgomery JA, Clayton SJ, Thomas HJ. Carbocyclic analog of 3-deazaadenosine - a novel antiviral agent using S-adenosylhomocysteine hydrolase as a pharmacological target. J Med Chem. 1982;25(6):626-629.
Crossref Google Scholar
42

Xiang S, Liang X, Yin S, Liu J, Xiang Z. N6-methyladenosine methyltransferase METTL3 promotes colorectal cancer cell proliferation through enhancing MYC expression. Am J Transl Res. 2020;12(5):1789-1806.
Google Scholar
43

Zhou L, Yang C, Zhang N, Zhang X, Zhao T, Yu J. Silencing METTL3 inhibits the proliferation and invasion of osteosarcoma by regulating ATAD2. Biomed Pharmacother. 2020;125:109964.
Crossref Google Scholar
44

Komala Sari T, Gianopulos KA, Nicola AV. Glycoprotein C of herpes simplex virus 1 shields glycoprotein B from antibody neutralization. J Virol. 2020;94(5):e01852-19.
Crossref Google Scholar
45

Cheng JT, Wang YY, Zhu LZ, et al. Novel transcription regulatory sequences and factors of the immune evasion protein ICP47 (US12) of herpes simplex viruses. Virol J. 2020;17(1):101.
Crossref Google Scholar
46

Goldsmith K, Chen W, Johnson DC, Hendricks RL. Infected cell protein (ICP)47 enhances herpes simplex virus neurovirulence by blocking the CD8+ T cell response. J Exp Med. 1998;187(3):341-348.
Crossref Google Scholar
47

Huang CY, Yao HW, Wang LC, Shen FH, Hsu SM, Chen SH. Thymidine kinase-negative herpes simplex virus 1 can efficiently establish persistent infection in neural tissues of nude mice. J Virol. 2017;91(4):e01979–16.
Crossref Google Scholar
48

Burrel S, Deback C, Agut H, Boutolleau D. Genotypic characterization of UL23 thymidine kinase and UL30 DNA polymerase of clinical isolates of herpes simplex virus: natural polymorphism and mutations associated with resistance to antivirals. Antimicrob Agents Chemother. 2010;54(11):4833-4842.
Crossref Google Scholar
49

Hao H, Hao S, Chen H. N6-methyladenosine modification and METTL3 modulate enterovirus 71 replication. Nucleic Acids Res. 2019;47(1):362-374.
Crossref Google Scholar
50

Kennedy EM, Bogerd HP, Kornepati AV, et al. Posttranscriptional m6A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe. 2016;19(5):675-685.
Crossref Google Scholar
51

Klupp BG, Baumeister J, Karger A, Visser N, Mettenleiter TC. Identification and characterization of a novel structural glycoprotein in pseudorabies virus, gL. J Virol. 1994;68(6):3868-3878.
Crossref Google Scholar
52

Reynolds AE, Ryckman BJ, Baines JD, Zhou Y, Liang L, Roller RJ. U(L)31 and U(L)34 proteins of herpes simplex virus type 1 form a complex that accumulates at the nuclear rim and is required for envelopment of nucleocapsids. J Virol. 2001;75(18):8803-8817.
Crossref Google Scholar
53

Hernández Durán A, Greco TM, Vollmer B, Cristea IM, Grünewald K, Topf M. Protein interactions and consensus clustering analysis uncover insights into herpesvirus virion structure and function relationships. PLoS Biol. 2019;17(6):e3000316.
Crossref Google Scholar
54

You H, Zheng S, Huang Z, Lin Y, Shen Q, Zheng C. Herpes simplex virus 1 tegument protein UL46 inhibits TANK-binding kinase 1-mediated signaling. mBio. 2019;10(3):e00919-19.
Crossref Google Scholar
55

Elliott GD. The extreme carboxyl terminus of the equine herpesvirus 1 homolog of herpes simplex virus VP16 is essential for immediate-early gene activation. J Virol. 1994;68(8):4890-4897.
Crossref Google Scholar
56

Tsai K, Courtney DG, Cullen BR. Addition of m6A to SV40 late mRNAs enhances viral structural gene expression and replication. PLoS Pathog. 2018;14(2):e1006919.
Crossref Google Scholar
57

Kennedy EM, Bogerd HP, Kornepati AV, et al. Posttranscriptional m(6)A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe. 2016;19(5):675-685.
Crossref Google Scholar
58

Tirumuru N, Zhao BS, Lu W, Lu Z, He C, Wu L. Correction: N(6)-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. Elife. 2017;6:e31482.
Crossref Google Scholar
59

Lichinchi G, Zhao BS, Wu Y, et al. Dynamics of human and viral RNA methylation during Zika virus infection. Cell Host Microbe. 2016;20(5):666-673.
Crossref Google Scholar
Genes & Diseases
Volume 9 Issue 4,
July 2022
Pages 1114-1128
DOI: 10.1016/j.gendis.2021.02.004
Cite this article:
Feng Z, Zhou F, Tan M, et al. Targeting m6A modification inhibits herpes virus 1 infection. Genes & Diseases, 2022, 9(4): 1114-1128. https://doi.org/10.1016/j.gendis.2021.02.004

318

Views

9

Downloads

28

Crossref

26

Web of Science

28

Scopus

0

CSCD

Altmetrics
Received: 30 September 2020
Revised: 26 January 2021
Accepted: 10 February 2021
Published: 22 February 2021
© 2021, Chongqing Medical University.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Return