Causes and Consequences of Flavivirus RNA Methylation

Abstract

Mosquito-borne flaviviruses are important human pathogens that represent global threats to human health. The genomes of these positive-strand RNA viruses have been shown to be substrates of both viral and cellular methyltransferases. N⁷-methylation of the 5' cap structure is essential for infection whereas 2'-O-methylation of the penultimate nucleotide is required for evasion of host innate immunity. N⁶-methylation of internal adenosine nucleotides has also been shown to impact flavivirus infection. Here, I summarize recent progress made in understanding roles for methylation in the flavivirus life-cycle and discuss relevant emerging hypotheses.

Keywords: Zika virus; dengue virus; flavivirus; hepatitis C virus; methylation.

FIGURE 1

Depiction of the flavivirus RNA capping and methylation pathway. Nascent flavivirus genomes initiate with a 5′ triphosphorylated adenosine that is dephosphorylated by the RNA triphosphatase (RTPase) activity of NS3. Next, the putative NS5 guanylyltransferase (GTase) attaches guanosine monophosphate (GMP) via a 5′-5′ linkage. NS5 then methylates the guanine N⁷ position to form the type 0 cap using S-adenosyl methionine (SAM) as a cofactor. Methyl group donation by SAM converts it to S-adenosyl homocysteine (SAH). NS5-mediated 2′-O-methylation of the adenosine nucleotide generates the type I cap structure. Finally, hypothetical m⁶A methylation of flaviviral RNA at the penultimate adenosine by the METTL3/14 protein complex would result in the formation m⁶Am.