It's Just a Phase: Exploring the Relationship Between mRNA, Biomolecular Condensates, and Translational Control

Abstract

Cells spatially organize their molecular components to carry out fundamental biological processes and guide proper development. The spatial organization of RNA within the cell can both promote and result from gene expression regulatory control. Recent studies have demonstrated diverse associations between RNA spatial patterning and translation regulatory control. One form of patterning, compartmentalization in biomolecular condensates, has been of particular interest. Generally, transcripts associated with cytoplasmic biomolecular condensates-such as germ granules, stress granules, and P-bodies-are linked with low translational status. However, recent studies have identified new biomolecular condensates with diverse roles associated with active translation. This review outlines RNA compartmentalization in various condensates that occur in association with repressed or active translational states, highlights recent findings in well-studied condensates, and explores novel condensate behaviors.

Keywords: P-bodies; biomolecular condensates; germ granules; mRNA localization; phase separation; stress granules; translation regulation.

FIGURE 1

P granules are nematode germ granules. (A) C. elegans P granules successively concentrate in the posterior P cells that eventually giving rise to the germline. nos-2 mRNA is found in the cytoplasm of 2-cell stage embryos in a translationally repressed state. From the 4-cell stage to the 28-cell stage, nos-2 mRNA concentrates into P granules though many nos-2 mRNA molecules also reside in the cytoplasm. nos-2 mRNA in P cells is spared from the degradation seen in somatic cells accounting for its concentration down the P lineage. At the 28-cell stage, nos-2 mRNA emerges from P granules and is translated. chs-1 mRNA also accumulates in P granules in a manner similar to nos-2 but is rapidly degraded. (B) Three cytoplasmic biomolecular condensates—P granules (germ granules), P-bodies, and stress granules—share key components and have some overlapping functions. Some proteins are distinct to each condensate. The components here represent diverse organisms and are not exhaustive.

FIGURE 2

The C. elegans P granule transcriptome has been characterized. (A) Lee et al. identified 492 transcripts enriched in P granules using an individual nucleotide resolution UV-crosslinking and precipitation (iCLIP) Lee et al. (2020a). (B) GO terms enriched in the C. elegans P granule transcriptome. We used Lee et al.’s expanded list of 492 MEG-3-associated P granule transcripts to identify enriched categories using the GO: TermFinder (Boyle et al., 2004); Lee et al. (2020a). Transcripts with greater than 10 transcripts per million at any embryonic stage from a previous single-cell resolution RNA-seq study (Hashimshony et al., 2015) were used as a background gene set. The negative log₁₀ of each p value is shown.

FIGURE 3

Condensates are associated with diverse forms of post-transcriptional regulation. (A) Saccharomyces cerevisiae translation factor granules are polarized translation factory condensates associated with translation at regions of growth. When the SHE2 or SHE3 genes are removed from cells, these condensates no longer polarize in lab or wild isolate strains. (B) Core Fermentation (CoFe) granules in S. cerevisiae are translation factory condensates associated with the translation of glycolytic components under fermentative conditions. (C) TIS granules in human cell lines are mesh-like condensates interweaved with the ER. In these condensates, TIS11B associates with AU rich elements present in the long 3′UTR isoform of CD47 to facilitate interaction with its effector protein, SET, upon translation. This condensate-associated interaction promotes increased association of CD47 protein with the cell membrane. (D) In human cells, the PCNT RNA is actively transported towards the centromere while translating to facilitate rapid incorporation into transient pericentriolar condensates. These condensates support the organization of the pericentriolar material and microtubules to allow mitosis to occur normally. (E) Dynein axonemal particles (DynAPs) spatially organize dynein proteins within a condensate environment to promote their appropriate assembly in a “reaction crucible” mechanism. When the condensate environment is disrupted through depletion of Heatr2, Dynein complex assembly is disrupted, axonemal Dynein organization is perturbed, and cilial beating is decreased. (F) The ß-catenin destruction complex is a condensate which forms throughout the cell cycle to degrade the constitutively translated ß-catenin protein. Upon induction of Wnt signaling, the components of the destruction complex are modified causing the complex to disassemble and become sequestered at the plasma membrane. When the destruction complex is sequestered, nascent ß-catenin protein can translocate to the nucleus to perform its functions in Wnt signaling.