The Roles of Host 5-Methylcytosine RNA Methyltransferases during Viral Infections.

Maciej Wnuk,Anna Lewinska,Piotr Slipek,Mateusz Dziedzic

doi:10.3390/ijms21218176

Maciej Wnuk, Anna Lewinska + Show 2 more

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https://doi.org/10.3390/ijms21218176

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Abstract

Eukaryotic 5-methylcytosine RNA methyltransferases catalyze the transfer of a methyl group to the fifth carbon of a cytosine base in RNA sequences to produce 5-methylcytosine (m5C). m5C RNA methyltransferases play a crucial role in the maintenance of functionality and stability of RNA. Viruses have developed a number of strategies to suppress host innate immunity and ensure efficient transcription and translation for the replication of new virions. One such viral strategy is to use host m5C RNA methyltransferases to modify viral RNA and thus to affect antiviral host responses. Here, we summarize the latest findings concerning the roles of m5C RNA methyltransferases, namely, NOL1/NOP2/SUN domain (NSUN) proteins and DNA methyltransferase 2/tRNA methyltransferase 1 (DNMT2/TRDMT1) during viral infections. Moreover, the use of m5C RNA methyltransferase inhibitors as an antiviral therapy is discussed.

Highlights

The development of molecular techniques has allowed for research intensification in the field of RNA modifications
Since the first report demonstrating chromatography-based detection of methylated cytosines in poly(A)-messenger RNA [2], m5C was detected in other types of RNA such as transfer RNA, ribosomal RNA, small nuclear RNA, microRNA, long noncoding RNA, transactivation response element (TAR), small vault RNA, and enhancer RNA of many organisms across all phylogenetic groups [3,4,5,6] Thanks to advances in RNA bisulfite sequencing, methylated RNA immunoprecipitation sequencing, and 5-azacytidine-mediated RNA immunoprecipitation or methylation-induced cross-linking immunoprecipitation, new qualitative and quantitative information about the target sites of RNA cytosine methyltransferases may be provided [7,8,9,10]
Here, we summarize the latest findings concerning the roles of m5C RNA methyltransferases during viral infections and suggest the use of m5C RNA methyltransferase inhibitors in antiviral therapies

Summary

Introduction

The development of molecular techniques has allowed for research intensification in the field of RNA modifications. We suggest that this modification may be important for genomic RNA stabilization, RNA transport to host cellular compartments, replication regulation, protection against degradation, and promotion of viral genetic heterogeneity that is based on cytidine deaminase activity. ERNA methylation stabilizes eRNA-bound protein complex and enhances RNA polymerase II activity [34] This may suggest the involvement of NSUN7 during metabolic reprogramming of infected cells as PGC-1α is robustly induced upon HCV infection [74] (Figure 1). MRNA expression microarray datasets from the Gene Expression Omnibus (GEO) database showed that expression levels of both 5-methylcytosine rRNA methyltransferase genes in cells infected with Ebola virus (EBOV) (GSE17509), influenza A virus (IAV) subtype H5N1 (A/H5N1) (GSE43302), SARS-BatS RBD (GSE47960), and HCV JFH-1 strain (GSE20948) were altered suggesting that NSUN3 and NSUN4 proteins are active members of the cellular viral response pathway. It is possible that DNMT2 and NSUN3 can be considered as new regulatory proteins in transcriptional process in the nucleus during cancer progression or chronic cellular stress [80] (Figure 1)

Attenuation of Host Antiviral Response by Virus-Mediated Activation of NSUN2

Inhibitors of m5C RNA Methyltransferases as Antiviral Drugs

Conclusions and Perspectives