Two Birds With One Stone: RNA Virus Strategies to Manipulate G3BP1 and Other Stress Granule Components

Stress granules (SGs) are membrane-less organelles forming in the cytoplasm in response to various types of stress, including viral infection. SGs and SG-associated proteins can play either a proviral role, by facilitating viral replication, or an antiviral role, by limiting the translation capacity, sequestering viral RNA, or contributing to the innate immune response of the cell. Consequently, viruses frequently target stress granules while counteracting cellular translation shut-off and the antiviral response. One strategy is to sequester SG components, not only to impair their assembly but also to repurpose and incorporate them into viral replication sites. G3BP1 is a key SG protein, driving its nucleation through protein-protein and protein-RNA interactions. Many cellular proteins, including other SG components, interact with G3BP1 via their ΦxFG motifs. Notably, SARS-CoV N proteins and alphaviral nsP3 proteins contain similar motifs, allowing them to compete for G3BP1. Several SG proteins have been shown to interact with the flaviviral capsid protein, which is primarily responsible for anchoring the viral genome inside the virion. There are also numerous examples of structured elements within coronaviral and flaviviral RNAs recruiting or sponging SG proteins. Despite these insights, the structural and biochemical details of SG-virus interactions remain largely unexplored and are known only for a handful of cases. Exploring their molecular relevance for infection and discovering new examples of direct SG-virus contacts is highly important, as advances in this area will open new possibilities for the design of targeted therapies and potentially broad-spectrum antivirals.