Alphavirus-induced transcriptional and translational shutoffs play major roles in blocking the formation of stress granules.

Our study highlights the mechanisms behind the cell's resistance to SG formation after infection with Old World alphaviruses. Shortly after infection, the replication of these viruses hinders the cell's ability to form SGs, even when exposed to chemical inducers such as sodium arsenite. This resistance is primarily attributed to virus-induced transcriptional and translational shutoffs, rather than interactions between the viral nsP3 and the key components of SGs, G3BP1/2, or the ADP-ribosylhydrolase activity of nsP3 macro domain. While interactions between G3BP and nsP3 are essential for the formation of viral replication complexes, their role in regulating SG development appears to be minimal, if any. Cells harboring replicating virus-specific RNA with modified abilities to inhibit transcription and/or translation, but encoding wt nsP3, retain the capacity for SG development. Understanding these mechanisms of regulation of SG development contributes to our knowledge of viral replication and the intricate relationships between alphaviruses and host cells.