The methyltransferase domain of the Sudan ebolavirus L protein specifically targets internal adenosines of RNA substrates, in addition to the cap structure

Martin, Baptiste; Coutard, Bruno; Guez, Théo; Paesen, Guido C; Canard, Bruno; Debart, Françoise; Vasseur, Jean-Jacques; Grimes, Jonathan M; Decroly, Etienne

RNA methylation also plays a key role in disguising viral RNAs as host 'self' RNAs, allowing them to escape host surveillance by intracellular sensors regulating interferon expression. Among them, Toll-like receptors and RIG-like cytosolic receptors such as RIG-I and MDA5 have been demonstrated to sense methylated RNA (56) (57) (58) (59) . Whereas RIG-I has been shown to detect 5 ends of mis-capped RNAs, MDA5 may play a key role in the detection of double-stranded RNA without internal methylations. It is also possible that interferon-stimulated genes (ISGs) or restriction factors could detect unmethylated RNAs as 'nonself', thereby limiting viral replication. Proteins from the IFIT family, for example, recognize the 5 end of triphosphate or mis-capped RNAs and block their translation into proteins (60, 61) . Another example is ADAR, a deaminase known to suppress filovirus replication by RNA editing (62, 63) , whose activity is hampered by the presence of 2 -OH methyl groups (64) . A role of 2'O-methylation in shielding the virus from the host's innate immunity system could also explain why replication of an EBOV minigenome is not inhibited by type I, type II or type III interferons (65) , even in the absence of VP24, which helps repress ISG expression (66, 67) . Future research is needed to further characterize the internal methylation of Ebola virus RNA and to elucidate its role in the live cycle and pathogenesis of the virus.