Characterisation of the Semliki Forest Virus-host cell interactome reveals the viral capsid protein as an inhibitor of nonsense-mediated mRNA decay

The positive-sense, single-stranded RNA alphaviruses pose a potential epidemic threat. Understanding the complex interactions between the viral and the host cell proteins is crucial for elucidating the mechanisms underlying successful virus replication strategies and for developing specific antiviral interventions. Here we present the first comprehensive protein-protein interaction map between the proteins of Semliki Forest Virus (SFV), a mosquito-borne member of the alphaviruses, and host cell proteins. Among the many identified cellular interactors of SFV proteins, the enrichment of factors involved in translation and nonsense-mediated mRNA decay (NMD) was striking, reflecting the virus' hijacking of the translation machinery and indicating viral countermeasures for escaping NMD by inhibiting NMD at later time points during the infectious cycle. In addition to observing a general inhibition of NMD about 4 hours post infection, we also demonstrate that transient expression of the SFV capsid protein is sufficient to inhibit NMD in cells, suggesting that the massive production of capsid protein during the SFV reproduction cycle is responsible for NMD inhibition. Author summary To take over control of the host cell and ensure its own replication, viral proteins do interact with a plethora of host cell proteins. Elucidating these viral-host cell protein interactions is therefore key for understanding the mechanisms that a virus applies to successfully hijack the host cell. This study provides the first comprehensive protein-protein interaction map between the proteins of Semliki Forest Virus (SFV), a positive-strand, single-stranded RNA virus of the alphavirus family. While we previously discovered that the host cell recognizes and degrades the incoming viral genomic RNA by a cellular quality control system called Nonsense-Mediated mRNA Decay (NMD), our interactome study now led to uncovering of the other side of this arms race between SFV and the infected cells: We show in this study that the viral capsid protein has the capacity to inhibit NMD.

Automated summary

Understanding the interactions between Semliki Forest Virus proteins and host cell proteins is crucial for understanding the mechanisms by which the virus replicates successfully and develops specific antiviral interventions. The study shows that the virus hijacks the translation machinery and inhibits NMD to escape the host cell's defense mechanisms, with the capsid protein playing a key role in inhibiting NMD during the infectious cycle.