Alphavirus nsP3 as a multifunctional orchestrator of virus-host interplay.

Alphaviruses can cause polyarthralgia and encephalitis and pose an escalating global health threat to humans and animals. They are transmitted to vertebrates mainly by infected mosquitoes, leading to host alternation that drives an evolutionary arms race between the virus and host, during which the virus is selected to efficiently utilize the cellular factors of both hosts for replication. Alphaviruses encode the information necessary for replication in their genomic viral RNA, which is translated into nonstructural proteins, such as nonstructural protein 3 (nsP3). nsP3 is a remarkably multifunctional protein that promotes replication of viral RNAs and translation through diverse mechanisms. Among these mechanisms, nsP3 serves as a hub to recruit host proteins, acts as an RNA-binding protein, removes post-translational modifications from host and viral proteins, and modulates cellular pathways and host immune responses. nsP3 oligomerizes into helical scaffolds present in both viral replication complexes and nsP3-positive condensates that form during infection. Although the importance of nsP3 is evident, many of its roles remain less well understood compared to those of other alphavirus proteins. Here, we provide an overview of the current knowledge on how nsP3 promotes virus replication and pathogenesis and influences host range specificity. Further studies on nsP3 are needed to elucidate its mechanisms of action in the alphavirus replication cycle, which may ultimately support new strategies for outbreak surveillance, prediction, and infection countermeasures.