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The RNA demethylase FTO controls m6A marking on SARS-CoV-2 and classifies COVID-19 severity in patients

Malbec, L.; Celerier, M.; Bizet, M.; Calonne, E.; Hofmann-Winkler, H.; Boeckx, B.; Abdelnabi, R.; Putmans, P.; Hassabi, B.; Naesens, L.; Lambrechts, D.; Pöhlmann, S.; Deplus, R.; Delang, L.; Jeschke, J.; Fuks, F.

2022-06-28 molecular biology
10.1101/2022.06.27.497749 bioRxiv
Show abstract

The RNA modification N6-methyladenosine (m6A) plays a key role in the life cycles of several RNA viruses. Whether this applies to SARS-CoV-2 and whether m6A affects the outcome of COVID-19 disease is still poorly explored. Here we report that the RNA demethylase FTO strongly affects both m6A marking of SARS-CoV-2 and COVID-19 severity. By m6A profiling of SARS-CoV-2, we confirmed in infected cultured cells and showed for the first time in vivo in hamsters that the regions encoding TRS_L and the nucleocapsid protein are multiply marked by m6A, preferentially within RRACH motifs that are specific to {beta}-coronaviruses and well conserved across SARS-CoV-2 variants. In cells, downregulation of the m6A demethylase FTO, occurring upon SARS-CoV-2 infection, increased m6A marking of SARS-CoV-2 RNA and slightly promoted viral replication. In COVID-19 patients, a negative correlation was found between FTO expression and both SARS-CoV-2 expression and disease severity. FTO emerged as a classifier of disease severity and hence a potential stratifier of COVID-19 patients.

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