Regulation of Viral Infection by the RNA Modification N6-Methyladenosine

Abstract

In recent years, the RNA modification N6-methyladenosine (m⁶A) has been found to play a role in the life cycles of numerous viruses and also in the cellular response to viral infection. m⁶A has emerged as a regulator of many fundamental aspects of RNA biology. Here, we highlight recent advances in techniques for the study of m⁶A, as well as advances in our understanding of the cellular machinery that controls the addition, removal, recognition, and functions of m⁶A. We then summarize the many newly discovered roles of m⁶A during viral infection, including how it regulates innate and adaptive immune responses to infection. Overall, the goals of this review are to summarize the roles of m⁶A on both cellular and viral RNAs and to describe future directions for uncovering new functions of m⁶A during infection.

Keywords: DNA viruses; N6-methyladenosine; RNA modifications; RNA viruses; innate immunity; m6A; post-transcriptional regulation.

Figure 1.

The cellular m6A machinery and functions of writers, erasers, and readers. (a) Structures of A and m6A. The methyl group is colored blue. METTL3 and METTL14 are the writer proteins that catalyze the covalent conversion of A to m6A on target RNAs. FTO and ALKBH5 are demethylases capable of removing the methylation. The function of m6A bearing RNAs is influenced by interaction with reader proteins. (b) ① m6A is co-transcriptionally added to RNA by a writer complex of proteins, which consists of METTL3, METTL14, and WTAP, as well as accessory factors that can determine RNA targeting. ② m6A can be removed from RNA by the demethylases FTO and ALKBH5. m6A reader proteins, such as the YTHDF proteins, mediate diverse post-transcriptional processes on m6A containing RNA including ③ alternative splicing and polyadenylation, ④ nuclear export and RNA localization, ⑤ alteration of RNA stability, ⑥ cap-independent translation, ⑦ cap-dependent translation, and ⑧ modulation of protein-RNA interactions via structural switches. Abbreviations: A, adenosine; mRNA, messenger RNA; m6A, N6-methyladenosine, m⁷G, 7-Methylguanosine.

Figure 2.

The cellular m6A machinery impacts the replication of viruses from diverse families. Here we describe the main findings of how m6A on viral RNA regulates infection. Manipulation of cellular writers, erasers, and readers of m6A reshapes virus infection with differential outcomes depending on virus studied and cell type used for experiments. Viruses in the Flaviviridae family (DENV, ZIKV, WNV, YFV, and HCV) are negatively regulated by m6A writers while replication of enterovirus 71 and influenza A virus is promoted by m6A. m6A modification of viral transcripts derived from retroviruses and DNA viruses also bear m6A. The impact of m6A on these viruses is dependent on the stage of the viral replication cycle examined, host tissue, and viral strain studied. Color legend: Orange, positive-sense RNA viruses; Yellow, negative-sense RNA virus; Red, retrovirus; Blue, partially double-stranded DNA virus; Green, double-stranded DNA viruses. Abbreviations: DENV, dengue virus; EV71, enterovirus 71; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV-1, human immunodeficiency virus-1; IAV, influenza A virus; KSHV, Kaposi’s sarcoma-associated herpesvirus; m6A, N6-methyladenosine; pgRNA, pregenomic RNA; RRE, Rev response element; SV40, simian virus 40; WNV, West Nile virus; YFV, yellow fever virus; ZIKV, Zika virus.