Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5

By Roland Züst, L. Cervantes-Barragan, M. Habjan, R. Maier, B. Neuman, J. Ziebuhr, Kristy J. Szretter, S. Baker, W. Barchet, Michael S. Diamond and 3 more. Nature Immunology, 2011

759 citations recorded by the source corpus.

The 5′ cap structures of higher eukaryote mRNAs have ribose 2′-O-methylation. Likewise, many viruses that replicate in the cytoplasm of eukaryotes have evolved 2′-O-methyltransferases to autonomously modify their mRNAs. However, a defined biological role for 2′-O-methylation of mRNA remains elusive. Here we show that 2′-O-methylation of viral mRNA was critically involved in subverting the induction of type I interferon. We demonstrate that human and mouse coronavirus mutants lacking 2′-O-methyltransferase activity induced higher expression of type I interferon and were highly sensitive to type I interferon. Notably, the induction of type I interferon by viruses deficient in 2′-O-methyltransferase was dependent on the cytoplasmic RNA sensor Mda5. This link between Mda5-mediated sensing of viral RNA and 2′-O-methylation of mRNA suggests that RNA modifications such as 2′-O-methylation provide a molecular signature for the discrimination of self and non-self mRNA.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f65f1e6af94696f40cb915e5fd2c0feb932c3934

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Andrew G. Harrison
2. Tao Lin
3. Penghua Wang
4. C. Reis e Sousa
5. Safia Deddouche
6. D. Goubau
7. Jacques Banchereau
8. Shizuo Akira

In Molecular Biology

1. G. B. Robb
2. Siu-Hong Chan
3. Anand Ramanathan
4. C. Reis e Sousa
5. Safia Deddouche
6. D. Goubau

Citations in the corpus

• Coronaviruses: An Overview of Their Replication and Pathogenesis (2015, neutral): “nsp16 2′-O-MT; shields viral RNA from MDA5 recognition [ 157 , 158 ]”
• Interferon-stimulated genes and their antiviral effector functions (2011, neutral): “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].”
• Cytosolic Sensing of Viruses (2013, background): “Both the murine norovirus 1 and the murine hepatitis virus also trigger an MDA5-dependent IFN response (McCartney et al., 2008; Roth-Cross et al., 2008; Züst et al., 2011).”
• mRNA capping: biological functions and applications (2016, background): “The ability to generate cap 0 and cap 1 RNAs in vitro have also been invaluable in researching the role of the G cap and its 2′O methylation in innate immunity (2,68,76,81).”
• Mechanisms of SARS-CoV-2 Transmission and Pathogenesis (2020, positive): “, HCoV-229E) and murine hepatitis virus (MHV) also compensate for the loss of many supplementary immunosuppressive proteins through capping viral mRNAs via nsp16 2′-O-methyltransferase (2′-O-MTase), and mutants lacking this activity exhibit diminished replication and dissemination in mice [112].”
• Coronavirus Pathogenesis (2011, background): “However, a subsequent reverse genetic studywith active-site mutants of HCoV-229E andMHV-A59 demonstrated that viruses-containingmutations that completely abrogated 20-OMT activity (D129A for HCoV-229E, D130A for MHV) were viable (Zust et al., 2011).”