The Emerging Role of RNA Modifications in the Regulation of Antiviral Innate Immunity

Abstract

Posttranscriptional modifications have been implicated in regulation of nearly all biological aspects of cellular RNAs, from stability, translation, splicing, nuclear export to localization. Chemical modifications also have been revealed for virus derived RNAs several decades before, along with the potential of their regulatory roles in virus infection. Due to the dynamic changes of RNA modifications during virus infection, illustrating the mechanisms of RNA epigenetic regulations remains a challenge. Nevertheless, many studies have indicated that these RNA epigenetic marks may directly regulate virus infection through antiviral innate immune responses. The present review summarizes the impacts of important epigenetic marks on viral RNAs, including N6-methyladenosine (m6A), 5-methylcytidine (m5C), 2ʹ-O-methylation (2ʹ-O-Methyl), and a few uncanonical nucleotides (A-to-I editing, pseudouridine), on antiviral innate immunity and relevant signaling pathways, while highlighting the significance of antiviral innate immune responses during virus infection.

Methyltransferases of Riboviria

“…Surveys of modified residues in virus mRNAs have recently found methyl groups attached not only to the few 5′-terminal residues, but also to the nucleosides (the base or the sugar) in the mRNA body (recently reviewed in [ 75 , 76 ]). Neither the extent and site-specificity of those modifications, nor their biological functions have been sufficiently studied.…”

The Impact of Epitranscriptomics on Antiviral Innate Immunity

“…The growing awareness of the potential that epitranscriptomics has for transcript regulation requires further investigation into its role in the innate immune response, and sensing in particular. Previous work has revealed that RNA cap methylations are important in self/non-self RNA discrimination [80][81][82][83]. Indeed, while capped cellular mRNAs do not trigger immune responses, uncapped pathogenic RNAs are recognized by cellular sensors and activate the IFN-I response [69,84].…”

“…Hence, since 2015, multiple studies have explored and investigated the role of epitranscriptomic modifications during viral infection. These studies pointed out that (i) genomic viral RNA can be modified, and that these modifications have a significant impact on their viral life cycle; (ii) viral transcripts can be methylated by the cellular machinery, and (iii) the general epitranscriptomic landscape of the cell changes rapidly during infection, either to promote viral replication by virus-mediated hijacking, or to respond to the invading pathogen and prevent its replication through innate defense mechanisms [59,83,99]. These observations paved the way for further investigations into the possible roles of epitranscriptomic modifications in tuning the antiviral response, which is the focus of the present work (Table 1).…”

The controversial role and therapeutic development of the m6A demethylase FTO in renal cell carcinoma

“…N 6 -methyladenosine (m 6 A), one of the most abundant epitranscriptomic modifications of messenger RNA (mRNA) and non-coding RNA (ncRNA) in eukaryotic cells, is its main substrate, making FTO the first m 6 A demethylase identified [6] . m 6 A modifications regulate almost every stage of RNA metabolism [7] , which in turn affects many biological processes including metabolism [8] , innate immunity [9] , DNA repair [10] , and programmed cell death [11] , as well as various diseases including obesity [12] and many types of cancers [13] . Not surprisingly, FTO, as one of only two known m 6 A erasers [14] , plays an important role in all of these biological processes and human diseases, particularly in cancers [15] .…”