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Review
, 21 (6), 661-669

Making the Mark: The Role of Adenosine Modifications in the Life Cycle of RNA Viruses

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Review

Making the Mark: The Role of Adenosine Modifications in the Life Cycle of RNA Viruses

Sarah R Gonzales-van Horn et al. Cell Host Microbe.

Abstract

Viral epitranscriptomics is a newly emerging field that has identified unique roles for RNA modifications in modulating life cycles of RNA viruses. Despite the observation of a handful of modified viral RNAs five decades ago, very little was known about how these modifications regulate viral life cycles, until recently. Here we review the pro- and anti-viral effects of methyl-6-adenosine in distinct viral life cycles, the role of 2' O-methyl modifications in RNA stability and innate immune sensing, and functions of adenosine to inosine modifications in retroviral life cycles. With roles for over 100 modifications in RNA still unknown, this is a rapidly emerging field that is destined to suggest novel antiviral therapies.

Keywords: 2′-O-methyl; A-to-I editing; Epitranscriptomics; RNA viruses; YTHDF readers; demethylase erasers; flaviviruses; methyl-6-adenonsine; methyltransferase writers; retroviruses.

Figures

Figure 1
Figure 1. Adenosine modifications and the respective enzymes that facilitate these chemical modifications
N6-methyladenosine and N6,2-O-dimethyladenosine are reversible RNA modifications, while inosine and 2′-O-methyladenoinse seem to be irreversible. Of the modifications listed, only 2′-O-methyltransferases are encoded by viral genes (WNV: West Nile Virus; DV: Dengue Virus; H-CoV: Human Coronavirus) further supporting the important role for this modification in modulating viral sensing by innate immune pathways.
Figure 2
Figure 2. Three current models for m6A-mediated regulation of the HIV-1 lifecycle
(A) m6A enhances HIV virus production (Lichinchi, et. al.). Stemloop II within the HIV Rev response element (RRE) is m6A methylated at two sites, which promotes the HIV-encoded RNA binding protein, Rev, to bind to the RRE and enhance RNA nuclear export into the cytoplasm. Depletion of the methyltransferases METTL3/14 suppressed HIV-1 RNA export and viral replication, suggesting that m6A modifications within the RRE are important for the HIV lifecycle. (B) m6A enhances HIV RNA replication (Kennedy et. al.). Like the model presented in (A), this second study confirmed that the presence of m6A enhances viral replication. Cellular m6A-modified HIV RNAs are bound by the reader YTHDF proteins, which promote HIV replication. Depletion of YTHDF proteins reduced viral RNA abundance and virus titers, as did mutating certain m6A-modified adenosine residues to guanines. (C) m6A enhances HIV mRNA translation, but m6A/YTHDF readers reduce HIV reverse transcription (Tirumuru et. al.). In contrast to the models presented in (A) and (B), m6A was found to enhance translation, but to suppress reverse transcription, suggesting a modular role in the HIV lifecycle depending on the replication step. Depletion of METTL3/14 resulted in a reduction of viral protein expression, while the depletion of YTHDF proteins enhanced HIV reverse transcription.
Figure 3
Figure 3. The role of methyltransferases and methyl reader proteins in regulating the HCV lifecycle
HCV RNA is modified at several adenosines (m6A) throughout the genome, and ablation of these modifications promotes viral replication and release from the cell. This process is modulated by YTHDF methyl readers sequestering m6A-modified HCV RNAs, preventing the localization and interaction with HCV Core protein at the lipid droplets and subsequent virus particle production. See text for further details.

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