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

Züst, R. et al. Nat. Immunol. 12, 137-144 (2011).

Speaker: Fu-I, Tsai (蔡馥儀)                                 Time: 15:10-16:00, June, 1, 2011

Commentator: Dr. Pin, Ling (凌斌 老師)            Place: Room 601

Abstract

In innate immunity, 5’-triphosphate group on single-stranded RNA was found to be recognized by cytoplasmic receptor RIG-I. Moreover, 2’-O-methylation of mRNA was considered as a molecular signature for distinction of immunological self and non-self¹. In this study, the authors show that ribose 2’-O-methylation on 5’ cap provides a molecular signature for another cytoplasmic sensor, Mda5. As coronaviruses had been found to encode 2’-O-methyltransferase associated with viral nonstructural protein 16 (nsp16), mutants of nsp16 such as human coronavirus D129A (HCoV D129A), mouse hepatitis virus D130A and Y15A (MHV D130A, Y15A), have showed loss or less 2’-O-methyltransferase ability by using vaccinia virus 2’-O-methyltransferase in vitro. Further experiments suggested that infection of macrophages by nsp16 mutants can induce higher expression of type I IFN but not detected in mda5-deficient macrophages. Furthermore, interferon regulatory factor 3 (IRF3), the transcription factor of type I IFN, didn’t translocate to nucleus in mda5 -deficient macrophages infected with MHV D130A. In addition, the viral titers decreased in HCoVD129A- and MHV D130A-infected macrophages which pretreated with IFN-α, and indicated that loss of 2’-O-methylation on viral RNA can trigger second antiviral mechanism induced by type I IFN. IFIT1, which is encoded by interferon-stimulated genes, can restrict the replication of nsp16 mutated virus. In conclusion, loss of 2’-O-methylation on mRNA can induce type I IFN expression in mda5-dependent manner, and type I IFN-mediated restriction of viral replication.

References

1. Daffis, S. et al. 2’-O methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature. 468, 452-456 (2010)