2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members

By S. Daffis, Kristy J. Szretter, Jill M. Schriewer, Jianqing Li, Soonjeon Youn, J. Errett, Tsai-Yu Lin, S. Schneller, Roland Züst, Hongping Dong and 9 more. Nature, 2010

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Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2′-O positions of the 5′ guanosine cap by specific nuclear and cytoplasmic methyltransferases (MTases), respectively. Whereas N-7 methylation is essential for RNA translation and stability, the function of 2′-O methylation has remained uncertain since its discovery 35 years ago. Here we show that a West Nile virus (WNV) mutant (E218A) that lacks 2′-O MTase activity was attenuated in wild-type primary cells and mice but was pathogenic in the absence of type I interferon (IFN) signalling. 2′-O methylation of viral RNA did not affect IFN induction in WNV-infected fibroblasts but instead modulated the antiviral effects of IFN-induced proteins with tetratricopeptide repeats (IFIT), which are interferon-stimulated genes (ISGs) implicated in regulation of protein translation. Poxvirus and coronavirus mutants that lacked 2′-O MTase activity similarly showed enhanced sensitivity to the antiviral actions of IFN and, specifically, IFIT proteins. Our results demonstrate that the 2′-O methylation of the 5′ cap of viral RNA functions to subvert innate host antiviral responses through escape of IFIT-mediated suppression, and suggest an evolutionary explanation for 2′-O methylation of cellular mRNA: to distinguish self from non-self RNA. Differential methylation of cytoplasmic RNA probably serves as an example for pattern recognition and restriction of propagation of foreign viral RNA in host cells.

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Citations in the corpus

Coronavirus Pathogenesis (2011, background): “The 2 0 -OMT activity of nsp16 was also demonstrated to play a key role in avoiding the antiviral effect of IFIT-2 (ISG54) and IFIT-1 (ISG56), two members of the IFIT family of proteins that play an important role in the development of an antiviral state after interferon treatment (Daffis et al., 20”
Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5 (2011, unknown): “The replication of encephalomyocarditis virus (family Picornaviridae) seems to be not restricted by IFIT proteins 28 ; however, infection with this virus is sensed through the Mda5 pathway 35 .”
mRNA capping: biological functions and applications (2016, unknown): “The RNA triphosphatase activity (TPase) removes the (cid:2) -phosphate from 5 (cid:2) triphosphate, generating a diphosphate 5 end and inorganic phosphate (reaction [1]).”
Interferon-stimulated genes and their antiviral effector functions (2011, unknown): “Using a genetics approach, two groups have recently demonstrated that certain viruses use a virally-encoded 2'O-methyltransferase to specifically evade inhibition by IFIT proteins [27,28].”
Structural basis for m7G recognition and 2′-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I (2016, unknown): “IFIT1 is an IFN stimulated receptor recently shown as a key player in the recognition of capped RNAs (24).”