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Sci. Signal., 8 February 2011
Vol. 4, Issue 159, p. ec40
[DOI: 10.1126/scisignal.4159ec40]

EDITORS' CHOICE

Immunology Wearing the Same Cap

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Hosts and their pathogens exist in a constant struggle, with the host evolving mechanisms to avoid or eliminate infection and the pathogens evolving mechanisms to subvert these processes and survive and reproduce (see García-Sastre). One strategy used by the virus is host mimicry, which compromises the ability of the cell to tell self from nonself. Züst et al. provide insight into a mechanism by which the host cell distinguishes self mRNA from viral RNA and finds that some viruses can modify their RNAs to resemble those of the host and thus evade induction of the antiviral response. Eukaryotic mRNAs are modified by a 5' "cap" that includes ribose-2'-O-methylation, among other modifications. Many cytoplasmic viruses encode enzymes that add similar modifications to the viral RNAs. Züst et al. showed that viruses engineered to be deficient in 2'-O-methyltransferase caused a greatly increased induction of the interferon response from infected cells and were inhibited from replicating in cells treated with interferon relative to cells infected with the parent viral strains. Cytoplasmic viruses are detected by host sensor proteins of the RIG-1 family, including RIG-1 and MDA5, which recognize viral RNA products, and the induction of interferon by the response to the ribose-2'-O-methylation–deficient viruses required MDA5. Nuclear translocation of a transcription factor that induces genes encoding interferons in response to the ribose-2'-O-methylation–deficient viral infection was also MDA5-dependent. In vivo, mice infected with the parent mouse hepatitis virus (MHV-A59) exhibited persistent infection in the spleen and liver, whereas the ribose-2'-O-methylation–deficient viruses were not detectable 48 hours after infection. Using two different mutations in the ribose-2'-O-methyltransferase, one that completely abrogated activity (MHV-D130A) and one that had reduced activity (MHV-Y15A), the authors showed that, both in vivo (mouse infection) and in vitro (infection of cultured cells), replication of the MHV-D130A mutant was more effectively inhibited, and the data suggested that there were two mechanisms by which loss of ribose-2'-O-methylation triggered antiviral signaling, one that depended on the initial induction of type 1 interferon and one that depended on the responsiveness to interferon signaling. Indeed, translation of RNAs lacking ribose-2'-O-methylation is inhibited by proteins of the IFIT family, which are encoded by interferon target genes, and cells deficient in IFIT-1 exhibited robust replication of the MHV-D130A mutant. Thus, ribose-2'-O-methylation allows viral RNAs both to escape detection by MDA5 and to avoid translation inhibition.

R. Züst, L. Cervantes-Barragan, M. Habjan, R. Maier, B. W. Neuman, J. Ziebuhr, K. J. Szretter, S. C. Baker, W. Barchet, M. S. Diamond, S. G. Siddell, B. Ludewig, V. Thiel, Ribose-2'-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat. Immunol. 12, 137–143 (2011). [PubMed]

A. García-Sastre, 2 methylate or not 2 methylate: Viral evasion of the type 1 interferon response. Nat. Immunol. 12, 114–115 (2011). [PubMed]

Citation: N. R. Gough, Wearing the Same Cap. Sci. Signal. 4, ec40 (2011).



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