TIA-1/TIAR in viral infections, a dynamic functional spectrum from antiviral defense to pro-viral subjugation

TIA-1 (T-cell intracellular antigen-1) and TIAR (TIA-1-related protein) are evolutionarily conserved RNA-binding proteins at the center of cellular stress responses. Through their N-terminal RNA recognition motifs and C-terminal prion-like domain (PLD), they regulate mRNA translation, splicing, and stability, and drive the assembly of stress granules (SGs) via liquid-liquid phase separation. During viral infection, TIA-1/TIAR function spans a continuum between antiviral defense and pro-viral subjugation, rather than acting as a simple binary switch. Their canonical antiviral role is to nucleate SGs that stall viral translation and act as platforms for innate immune signaling. Viruses, in turn, disrupt these defenses in a temporal hierarchy: they first target the direct RNA regulatory functions of TIA-1/TIAR and later dismantle the SG platform. Viral RNA structures can act as high-affinity baits, competitively recruiting these proteins away from SGs and toward viral replication centers. Viral proteases can cleave key SG nucleators to dismantle the antiviral platform while sparing TIA-1/TIAR for pro-viral function. Here, we review the molecular mechanisms that underlie this functional spectrum in infections by diverse viruses. We propose and refine a “competitive subcellular compartmentalization” model, wherein the outcome of infection is shaped by a molecular tug-of-war for TIA-1/TIAR between antiviral SGs and pro-viral replication complexes. In physicochemical terms, disparate viral strategies can be unified as perturbations that lower the threshold for phase separation, shifting the equilibrium toward pro-viral condensates. Finally, we discuss the therapeutic potential of targeting this central host–virus interface.