High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies.
Ji-Young Youn et al. Molecular Cell 69:517 (2018)
Anne-Claude Gingras’ lab
Post-transcriptional regulation of mRNA is a complex process that occurs in distinct compartments within the cell. This compartmentalization can involve liquid-liquid phase separation (LLPS) into distinct RNA-associated bodies and granules. Cytosolic P-bodies and stress granules, which are respectively associated with mRNA degradation and storage, form by the coalescence of non-translating mRNA and associated proteins. Stress granules have recently become implicated in neurodegenerative disease as several ALS (amyotrophic lateral sclerosis) and FTD (Frontotemporal Dementia)-linked proteins localize to them. Mutations in these ALS/FTD-linked proteins have also been shown to promote stable LLPS events both in vivo and in vitro, simulating protein aggregates found in ALS/FTD patients. Despite the recent growing interest in these bodies and granules it has been technically challenging to systematically characterize them in vivo.
A new study from the Gingras lab (Youn et al., 2018), published in Molecular Cell, aimed to uncover the composition and the relative structural organization of P-bodies and stress granules. To accomplish this, Youn et al. employed a proteomics technique called BioID which detects proximal associations between proteins within a ~10nm radius in living human cells. By performing BioID on 119 different proteins associated with RNA-associated bodies and granules, Youn et al. were able to discover new components of stress granules and P-bodies and define the spatial organization of these structures. One surprising finding is that stress granules, which require stress induction to form visible structures through LLPS, already make proximal contacts in the absence of exogenous stress. These pre-existing contacts suggest that stress granule proteins already form densely connected networks in the absence of stress, thus allowing a rapid transition into microscopically visible granules upon stress. The findings in this paper offer new avenues for identifying the factors that induce the transition into microscopically visible stress granules and provide new opportunities for exploring the mechanisms that promote ALS/FTD pathologies.
The first author of the study, Dr. Ji-Young Youn, has been highlighted by Molecular Cell in the feature “Meet the Author”.