![]() Their assembly is triggered by various intracellular and extracellular stressors such as reactive oxygen species, heat, starvation, and viral infection. Translational arrest is a common stress response in eukaryotic cells that results in the cytosolic accumulation of non-membranous, untranslated ribonucleoprotein (RNP) aggregates called stress granules (SGs). Collectively, these results reveal that the enzymatic activity of DDX3 is required for the assembly of SGs and pharmacological inhibition of DDX3 could be relevant for the treatment of SG-dependent pathologies. RNA-mediated knockdown of DDX3 caused a similar reduction in SG assembly and minimal effect on SG disassembly. In contrast, both compounds only marginally affect the disassembly of SGs. We find that both DDX3 inhibitors reduce the assembly of SGs, with a more pronounced reduction from RK-33. We use two small molecule inhibitors of DDX3, RK33 and 16D, with distinct inhibitory mechanisms that target DDX3’s ATPase activity and RNA helicase site, respectively. Here, we address this question by determining the effects of DDX3 inhibition on the dynamics of SG assembly and disassembly. DDX3 plays a critical role in RNA metabolism, including SGs, but the role of DDX3 enzymatic activity in SG dynamics is not well understood. DEAD-Box RNA helicase 3 (DDX3) is an active target of drug development for the treatment of viral infections, cancers, and neurodegenerative diseases. Stress granules (SGs) are non-membranous cytosolic protein-RNA aggregates that process mRNAs through stalled translation initiation in response to cellular stressors and in disease.
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