Chronic stress antagonizes formation of stress granules

Stress granules (SGs) are cytoplasmic ribonucleoprotein condensates formed in response to stress-induced inhibition of mRNA translation and polysome disassembly. Despite the broad interest in SG assembly and disassembly in response to acute stress, SG dynamics under chronic stress has not been extensively investigated. We show that cells pre-conditioned with low-dose chronic (24 h exposure) stresses of various natures fail to assemble SGs in response to acute stress. While protein synthesis is drastically decreased by acute stress in pre-conditioned cells, polysome profiling analysis reveals the partial preservation of polysomes. Mechanistically, chronic stress slows down the rate of mRNA translation at the elongation phase, and triggers phosphorylation of translation elongation factor eEF2. These events further promote ribosome stalling, which is distinct from ribosome collisions known to trigger ribosome-associated quality-control pathways. In summary, chronic stress triggers ribosome stalling, which prevents efficient polysome disassembly and SG formation by subsequent acute stress.