Coupling of translation quality control and mRNA targeting to stress granules

Abstract Stress granules (SGs) are dynamic assemblies of non-translating RNAs and proteins that form with translation inhibition1. Stress granules are similar to neuronal and germ cell granules, play a role in survival during stress, and aberrant, cytotoxic SGs are implicated in neurodegeneration2–4. Perturbations in the ubiquitin-proteasome (UPS) system also cause neurodegeneration5–10, and alter the dynamicity and kinetics of SGs11–14. Using single mRNA imaging in live cells15, 16, we took an unbiased approach to determine if defects in the UPS perturb mRNA translation and partitioning into SGs during acute stress. We observe ribosomes stall on mRNAs during arsenite stress, and the release of transcripts from stalled ribosomes for their partitioning into SGs requires the activities of valosin-containing protein (VCP) and the proteasome, which is in contrast to previous work showing VCP primarily affected SG disassembly 11, 13, 14, 17. Moreover, members of a specialized complex in the UPS that targets aberrant nascent proteins for decay upon ribosome stalling, referred to as ribosome-associated quality control complex (RQC)18, are also required for mRNA release from ribosomes and partitioning into SGs. VCP alleles that increase segregase activity and cause neurodegeneration and inclusion body myopathies5, 6, 19, 20 increase mRNA recruitment to SGs, suggesting aberrant mRNA localization to SGs in disease contexts. This work identifies a new type of stress-activated RQC (saRQC) distinct from canonical RQC pathways in mRNA substrates, cellular context and mRNA fate.