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), 2'-O-methylation (2'-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.

Keywords: IFN-I; RIG-I; RNA modification; antiviral innate immunity; viral infection.

Figure 1

Brief summary of RNA modifications in regulating virus infection. N6-methyladenosine (m⁶A), 5-methylcytidine (m⁵C), 2ʹ-O-methylation (2ʹ-O-Me)/7-methylguanosine (m⁷G), and A-to-I editing (A-to-I) are listed as example of epigenetic regulations in virus infection. Three major effects are summarized in diverse virus infection, among which the modulation of innate immune response is the focus of the present review. T. B. D: To be determined. References are listed in the Supplementary Table S1.

Figure 2

Schematic diagram of mechanisms by which RNA modification regulating viral-derived RNA recognition and innate immune responses. N⁶-methyladenosine (m⁶A), 5-methylcytidine (m⁵C), 2ʹ-O-methylation (2ʹ-O-Me), and pseudouridine (ψ) are demonstrated to inhibit melanoma differentiation-associated protein 5 (MDA5) or retinoic acid-inducible gene I (RIG-I) mediated sensing. METTL and YTHDF proteins are involved in these process. Inside the endosomes, 2′-O-Me are identified to block the TLR7-dependent type I interferon (IFN-I) response. Meanwhile, m⁶A, m⁵C, and ψ also prevent the Toll-like receptors (TLRs) activation inside the endosomes, although the relevance to virus infection still remains ambiguous. Moreover, m⁶A may regulate antiviral innate immunity through stress granules or endoplasmic reticulum (ER)-stress pathways, the latter of which has already been illustrated in Flavivirus infection.