N6-methyladenosine modification and METTL3 modulate enterovirus 71 replication

Abstract

N 6-methyladenosine (m6A) constitutes one of the most abundant internal RNA modifications and is critical for RNA metabolism and function. It has been previously reported that viral RNA contains internal m6A modifications; however, only recently the function of m6A modification in viral RNAs has been elucidated during infections of HIV, hepatitis C virus and Zika virus. In the present study, we found that enterovirus 71 (EV71) RNA undergoes m6A modification during viral infection, which alters the expression and localization of the methyltransferase and demethylase of m6A, and its binding proteins. Moreover, knockdown of m6A methyltransferase resulted in decreased EV71 replication, whereas knockdown of the demethylase had the opposite effect. Further study showed that the m6A binding proteins also participate in the regulation of viral replication. In particular, two m6A modification sites were identified in the viral genome, of which mutations resulted in decreased virus replication, suggesting that m6A modification plays an important role in EV71 replication. Notably, we found that METTL3 interacted with viral RNA-dependent RNA polymerase 3D and induced enhanced sumoylation and ubiquitination of the 3D polymerase that boosted viral replication. Taken together, our findings demonstrated that the host m6A modification complex interacts with viral proteins to modulate EV71 replication.

Functions of N6-methyladenosine and its role in cancer

“…METTL3 facilitates the stability of viral RNAdependent RNA polymerase 3D and boosts type 71 enterovirus replication by inducing sumoylation and ubiquitination of the polymerase [53].…”

RNA N6-Methyladenosine Modifications and the Immune Response

“…Although the mechanism remains uncertain, one assumption is that YTHDF2 promotes the degradation of antiviral gene transcripts [62]. Third, m 6 A modifications play a positive role in enterovirus 71 (EV71) replication [63]. Fourth, m 6 A modifications impair viral replication by blocking the packaging of viral RNA into new virions during flavivirus infections [64].…”

Extensive epitranscriptomic methylation of A and C residues on murine leukemia virus transcripts enhances viral gene expression

“…Previously, we reported that m 6 A residues enhance viral gene expression and replication for HIV-1, influenza A virus and the polyoma virus SV40 (9–11) and others have also reported that m 6 A residues promote HIV-1 and enterovirus 71 replication (12, 13) and play a role in the activation of lytic replication in Kaposi’s sarcoma herpesvirus (KSHV)-infected cells (14, 15). More recently, we reported that addition of m 5 C also enhances HIV-1 gene expression (8), and others have reported that Nm modifications on HIV-1 transcripts promote HIV-1 replication by inhibiting the detection of viral transcripts by the innate antiviral RNA sensor MDA5 (16).…”