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Brief description/objective

Eukaryotic messenger RNAs (mRNAs) play a universal role as transcripts of the genomic information that is used for the translation into proteins of a cell. Similarly, viruses that infect eukaryotic host cells produce viral mRNAs from their genome in order to translate them into viral proteins. Therefore, the host cell aims to distinguish self from non-self mRNA – a process that is used to recognize an ongoing infection – in order to initiate antiviral effector mechanisms in the context of the so-called “innate immune response”. Higher eukaryotic cellular mRNAs are characterized by a 5'-cap structure that is methylated at the capping guanosine N-7-position, and at the ribose 2'-O-position of the first and in some instances additional nucleosides. A number of viruses replicating in the cytoplasm (e.g. coronaviruses) have evolved enzymatic functions, such as N-7 and 2'-O-methyltransferases (MTases), to synthesize viral mRNAs containing these RNA modifications. The current project aims to investigate the impact N7- and 2’O-methylation of viral and cellular mRNAs on two fundamental cellular processes, namely (mRNA 5’-cap-dependent) protein synthesis and the detection of molecular signatures for non-self RNA recognition. By using defined coronavirus mutants with inactivated MTases which produce viral mRNAs lacking N7- and/or 2'-O-methylation, we will assess the biological significance of mRNA methylation. We expect that our studies will provide general insights into the biology of mRNA sensing and translation in eukaryotic cells.