Skip to main content
Top
Published in: BMC Oral Health 1/2023

Open Access 01-12-2023 | Herpes Virus | Research

Promotion of the resistance of human oral epithelial cells to herpes simplex virus type I infection via N6-methyladenosine modification

Authors: Junping Xu, Yuping Qi, Qi Ju

Published in: BMC Oral Health | Issue 1/2023

Login to get access

Abstract

Objective

This study aimed to explore the mechanism behind N6-methyladenosine (m6A) modification of the total ribonucleic acid (RNA) involved in the resistance to herpes simplex virus type I (HSV-1) infection in oral epithelial cells.

Method

The variation in m6A modification level on messenger RNA following HSV-1 infection was determined using the RNA dot blot method. The expression levels of alpha-ketoglutarate-dependent dioxygenase lab homolog 5 (ALKBH5) protein and fatty mass and obesity-associated genes (FTO) were determined using real-time fluorescence quantification polymerase chain reaction and the western blot technique, respectively. Next, after suppressing the expression of ALKBH5 or FTO via small interfering RNA, human immortalised oral epithelial cells (HIOECs) were infected with HSV-1, followed by measurement of the viral load or expression level of type I interferon (I-IFN) and interferon-stimulated genes (ISGs).

Results

The m6A modification level was significantly increased following HSV-1 infection of the HIOECs (P < 0.05), while the expression of ALKBH5 and FTO genes was reduced (P < 0.01). Moreover, the suppression of ALKBH5 or FTO increased the production of I-IFN and ISGs during the HSV-1 infection of the HIOECs (P < 0.01), and the viral load was significantly reduced (P < 0.01).

Conclusion

During oral HSV-1 infection, the m6A level was increased through the down-regulation of ALBHK5 and FTO expression, increasing I-IFN production and the promotion of HSV-1 clearing in HIOECs.
Literature
1.
go back to reference Balasubramaniam R, Kuperstein AS, Stoopler ET. Update on oral herpes virus infections. Dent Clin N Am. 2014;58(2):265–80.CrossRefPubMed Balasubramaniam R, Kuperstein AS, Stoopler ET. Update on oral herpes virus infections. Dent Clin N Am. 2014;58(2):265–80.CrossRefPubMed
2.
go back to reference Naveen-Kumar B, Tatapudi R, Sudhakara-Reddy R, et al. Various forms of tobacco usage and its associated oral mucosal lesions. J Clin Exp Dent. 2016;8(2):e172–7.PubMedPubMedCentral Naveen-Kumar B, Tatapudi R, Sudhakara-Reddy R, et al. Various forms of tobacco usage and its associated oral mucosal lesions. J Clin Exp Dent. 2016;8(2):e172–7.PubMedPubMedCentral
3.
go back to reference Luo Y, Xiong D, Li HH, Qiu SP, Lin CL, Chen Q, Huang CH, Yuan Q, Zhang J, Xia NS. Development of an HSV-1 neutralization test with a glycoprotein D specific antibody for measurement of neutralizing antibody titer in human sera. Virol J. 2016;13:44.CrossRefPubMedPubMedCentral Luo Y, Xiong D, Li HH, Qiu SP, Lin CL, Chen Q, Huang CH, Yuan Q, Zhang J, Xia NS. Development of an HSV-1 neutralization test with a glycoprotein D specific antibody for measurement of neutralizing antibody titer in human sera. Virol J. 2016;13:44.CrossRefPubMedPubMedCentral
5.
6.
go back to reference Zheng W, Chu Q, Yang LY, Sun LP, Xu TJ. Circular RNA circDtx1 regulates IRF3-mediated antiviral immune responses through suppression of miR-15a-5p-dependent TRIF downregulation in teleost fish. PLoS Pathog. 2021;17(3):e1009438.CrossRefPubMedPubMedCentral Zheng W, Chu Q, Yang LY, Sun LP, Xu TJ. Circular RNA circDtx1 regulates IRF3-mediated antiviral immune responses through suppression of miR-15a-5p-dependent TRIF downregulation in teleost fish. PLoS Pathog. 2021;17(3):e1009438.CrossRefPubMedPubMedCentral
7.
go back to reference Guo BZ, Zhang HL, Wang JL, Wu RLG, Zhang JY, Zhang QQ, Xu L, Shen M, Zhang ZB, Gu FY, Zeng WL, Jia XD, Yin CL. Identification of the signature associated with m(6)A RNA methylation regulators and m(6)A-related genes and construction of the risk score for prognostication in early-stage lung adenocarcinoma. Front Genet. 2021;12:656114.CrossRefPubMedPubMedCentral Guo BZ, Zhang HL, Wang JL, Wu RLG, Zhang JY, Zhang QQ, Xu L, Shen M, Zhang ZB, Gu FY, Zeng WL, Jia XD, Yin CL. Identification of the signature associated with m(6)A RNA methylation regulators and m(6)A-related genes and construction of the risk score for prognostication in early-stage lung adenocarcinoma. Front Genet. 2021;12:656114.CrossRefPubMedPubMedCentral
8.
go back to reference Zhang ZJ, Luo KX, Zou ZY, Qiu MGY, Tian JK, Sieh L, Shi HL, Zou YX, Wang G, Morrison J, Zhu AC, Qiao M, Li ZS, Stephens M, He X, He C. Genetic analyses support the contribution of mRNA N(6)-methyladenosine (m(6)A) modification to human disease heritability. Nat Genet. 2020;52(9):939–49.CrossRefPubMedPubMedCentral Zhang ZJ, Luo KX, Zou ZY, Qiu MGY, Tian JK, Sieh L, Shi HL, Zou YX, Wang G, Morrison J, Zhu AC, Qiao M, Li ZS, Stephens M, He X, He C. Genetic analyses support the contribution of mRNA N(6)-methyladenosine (m(6)A) modification to human disease heritability. Nat Genet. 2020;52(9):939–49.CrossRefPubMedPubMedCentral
10.
go back to reference Wang W, Shao F, Yang XY, Wang JH, Zhu RX, Yang YN, Zhao GX, Guo D, Sun YL, Wang J, Xue Q, Gao SG, Gao YB, He J, Lu ZM. METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding. Nat Commun. 2021;12(1):3803.CrossRefPubMedPubMedCentral Wang W, Shao F, Yang XY, Wang JH, Zhu RX, Yang YN, Zhao GX, Guo D, Sun YL, Wang J, Xue Q, Gao SG, Gao YB, He J, Lu ZM. METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding. Nat Commun. 2021;12(1):3803.CrossRefPubMedPubMedCentral
11.
12.
go back to reference Li J, Zhu LJ, Shi YH, Liu JN, Lin L, Chen X. m6A demethylase FTO promotes hepatocellular carcinoma tumorigenesis via mediating PKM2 demethylation. Am J Transl Res. 2019;11(9):6084–92.PubMedPubMedCentral Li J, Zhu LJ, Shi YH, Liu JN, Lin L, Chen X. m6A demethylase FTO promotes hepatocellular carcinoma tumorigenesis via mediating PKM2 demethylation. Am J Transl Res. 2019;11(9):6084–92.PubMedPubMedCentral
13.
go back to reference Ling Z, Chen L, Zhao J. m6A-dependent up-regulation of DRG1 by METTL3 and ELAVL1 promotes growth, migration, and colony formation in osteosarcoma. Biosci Rep. 2020;40(4):BSR20200282.CrossRef Ling Z, Chen L, Zhao J. m6A-dependent up-regulation of DRG1 by METTL3 and ELAVL1 promotes growth, migration, and colony formation in osteosarcoma. Biosci Rep. 2020;40(4):BSR20200282.CrossRef
14.
go back to reference Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, Huang H, Nachtergaele S, Dong L, Hu C, Qin X, Tang L, Wang Y, Hong GM, Huang H, Wang X, Chen P, Gurbuxani S, Arnovitz S, Li Y, Li S, Strong J, Neilly MB, Larson RA, Jiang X, Zhang P, Jin J, He C, Chen J. FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell. 2017;31(1):127–41.CrossRefPubMed Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, Huang H, Nachtergaele S, Dong L, Hu C, Qin X, Tang L, Wang Y, Hong GM, Huang H, Wang X, Chen P, Gurbuxani S, Arnovitz S, Li Y, Li S, Strong J, Neilly MB, Larson RA, Jiang X, Zhang P, Jin J, He C, Chen J. FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell. 2017;31(1):127–41.CrossRefPubMed
15.
go back to reference Su R, Dong L, Li CY, Nachtergaele S, Wunderlich M, Qing Y, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell. 2018;172(1):90–105.CrossRefPubMed Su R, Dong L, Li CY, Nachtergaele S, Wunderlich M, Qing Y, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell. 2018;172(1):90–105.CrossRefPubMed
16.
go back to reference Selberg S, Seli N, Kankuri E, Karelson M. Rational design of novel anticancer small-molecule RNA m6A demethylase ALKBH5 inhibitors. ACS Omega. 2021;6(20):13310–20.CrossRefPubMedPubMedCentral Selberg S, Seli N, Kankuri E, Karelson M. Rational design of novel anticancer small-molecule RNA m6A demethylase ALKBH5 inhibitors. ACS Omega. 2021;6(20):13310–20.CrossRefPubMedPubMedCentral
17.
go back to reference Heck AM, Russo J, Wilusz J, Nishimura EO, Wilusz CJ. YTHDF2 destabilizes m(6)A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells. RNA. 2020;26(6):739–55.CrossRefPubMedPubMedCentral Heck AM, Russo J, Wilusz J, Nishimura EO, Wilusz CJ. YTHDF2 destabilizes m(6)A-modified neural-specific RNAs to restrain differentiation in induced pluripotent stem cells. RNA. 2020;26(6):739–55.CrossRefPubMedPubMedCentral
18.
go back to reference Mapperley C, Van De Lagemaat LN, Lawson H, Tavosanis A, Paris J, Campos J, et al. The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function. J Exp Med. 2021;218(3):e20200829.CrossRefPubMedCentral Mapperley C, Van De Lagemaat LN, Lawson H, Tavosanis A, Paris J, Campos J, et al. The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function. J Exp Med. 2021;218(3):e20200829.CrossRefPubMedCentral
20.
21.
go back to reference Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol. 2007;57(5):737–63.CrossRefPubMed Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol. 2007;57(5):737–63.CrossRefPubMed
23.
24.
go back to reference Qin Y, Li L, Luo E, Hou J, Yan G, Wang D, Qiao Y, Tang C. Role of m6A RNA methylation in cardiovascular disease (Review). Int J Mol Med. 2020;46(6):1958–72.CrossRefPubMedPubMedCentral Qin Y, Li L, Luo E, Hou J, Yan G, Wang D, Qiao Y, Tang C. Role of m6A RNA methylation in cardiovascular disease (Review). Int J Mol Med. 2020;46(6):1958–72.CrossRefPubMedPubMedCentral
25.
go back to reference Sun T, Wu R, Ming L. The role of m6A RNA methylation in cancer. Biomed Pharmacother. 2019;112:108613.CrossRefPubMed Sun T, Wu R, Ming L. The role of m6A RNA methylation in cancer. Biomed Pharmacother. 2019;112:108613.CrossRefPubMed
26.
go back to reference Xu K, Mo Y, Li D, Yu QM, Wang L, Lin FH, Kong C, Balelang MF, Zhang AQ, Chen SJ, Dai QX, Wang JL. N(6)-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury. Ther Adv Chronic Dis. 2020;11:2040622320916024.CrossRefPubMedPubMedCentral Xu K, Mo Y, Li D, Yu QM, Wang L, Lin FH, Kong C, Balelang MF, Zhang AQ, Chen SJ, Dai QX, Wang JL. N(6)-methyladenosine demethylases Alkbh5/Fto regulate cerebral ischemia-reperfusion injury. Ther Adv Chronic Dis. 2020;11:2040622320916024.CrossRefPubMedPubMedCentral
27.
go back to reference Zhang C, Samanta D, Lu H, Bullen JW, Zhang HM, Chen I, He XS, Semenza GL. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proc Natl Acad Sci USA. 2016;113(14):E2047-2056.CrossRefPubMedPubMedCentral Zhang C, Samanta D, Lu H, Bullen JW, Zhang HM, Chen I, He XS, Semenza GL. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proc Natl Acad Sci USA. 2016;113(14):E2047-2056.CrossRefPubMedPubMedCentral
28.
go back to reference Li Z, Weng H, Su R, Weng X, Zuo Z, Li C. FTO Plays an oncogenic role in acute myeloid leukemia as a N(6)-methyladenosine RNA demethylase. Cancer Cell. 2017;31(1):127–41.CrossRefPubMed Li Z, Weng H, Su R, Weng X, Zuo Z, Li C. FTO Plays an oncogenic role in acute myeloid leukemia as a N(6)-methyladenosine RNA demethylase. Cancer Cell. 2017;31(1):127–41.CrossRefPubMed
29.
go back to reference Wu BX, Su SC, Patil DP, Liu HH, Gan JH, Jaffrey SR, Ma JB. Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1. Nat Commun. 2018;9(1):420–420.CrossRefPubMedPubMedCentral Wu BX, Su SC, Patil DP, Liu HH, Gan JH, Jaffrey SR, Ma JB. Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1. Nat Commun. 2018;9(1):420–420.CrossRefPubMedPubMedCentral
30.
go back to reference Zhang S, Zhao BS, Zhou A, Lin KY, Zheng SP, Lu ZK, et al. m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31(4):591–606.CrossRefPubMedPubMedCentral Zhang S, Zhao BS, Zhou A, Lin KY, Zheng SP, Lu ZK, et al. m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31(4):591–606.CrossRefPubMedPubMedCentral
Metadata
Title
Promotion of the resistance of human oral epithelial cells to herpes simplex virus type I infection via N6-methyladenosine modification
Authors
Junping Xu
Yuping Qi
Qi Ju
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Oral Health / Issue 1/2023
Electronic ISSN: 1472-6831
DOI
https://doi.org/10.1186/s12903-023-02744-2

Other articles of this Issue 1/2023

BMC Oral Health 1/2023 Go to the issue