Modulation of RNA condensation by the eIF4A RNA helicase
Posted on: 1 August 2019 , updated on: 8 August 2019
Preprint posted on 2 July 2019
Article now published in Cell at http://dx.doi.org/10.1016/j.cell.2019.12.031
RNA helicase eIF4A limits RNA-RNA interaction to reduce stress granule formation.
Selected by Nidhi Kanwal
Categories: biochemistry, cell biology, molecular biology
Background
In a heathy cell, hundreds of mRNAs and proteins interact with each other to maintain cellular homeostasis. However, in response to an insult, these cellular mRNAs and proteins can condense to partition out of the rest of the cytoplasm to form membrane-less cellular foci. These foci, termed stress granules (SG) or P-bodies, are mediated by liquid-liquid phase separation and can perturb the distribution and localization of RNAs. SGs are typically induced in response to translational arrest and harbor translation initiation factors and RNA helicases, whereas P-bodies are enriched in mRNA decay factors and thus serve as hotspots for mRNA decay. Recent evidence shows that RNA-RNA interactions without proteins can alone seed foci for the formation of SGs in vitro. Also, the high abundance of RNA helicases, proteins that unwind RNA, in SGs prompted the authors to hypothesize that alleviating RNA-RNA interaction could be a mechanism to limit the formation of the SGs. The present preprint focuses on the helicase, eIF4A, and demonstrates its role as an ‘RNA decondensase’ in limiting the formation of SGs.
Key findings
Tauber et al. used combinations of labelled polyA, polyU and polyC oligos, and mRNAs to check for their in vitro condensation by immunofluorescence. They showed that RNA-RNA interaction at the surface of a condensate, even in the absence of proteins, is thermodynamically favored and can cause concentration of RNA/RNP in the cells. Therefore, they speculated the existence of cellular mechanisms to limit this interaction. Since RNA helicases are enriched in SGs, they propose that they act as ‘RNA decondensases’ to limit RNA-RNA interaction by showing that:
- eIF4A helicase activity limits RNP partitioning into the stress granules
Owing to the presence of eIF4A at the periphery of SGs, the authors decided to investigate the roles of eIF4A in limiting RNA-RNA interaction at the surface of SGs. They showed that under arsenite stress, an established inducer of SG formation, eIF4A partitions into SGs and its inhibition leads to increased RNA partitioning as monitored by single molecule FISH (smFISH). By using hippuristanol or Pateamine A (PatA), drugs that specifically inhibit the helicase activity of eIF4A or its function in translation initiation, respectively, they showed that inhibition of eIF4A helicase activity (but not its translational activity) increases RNA partitioning into SGs.
- eIF4A limits stress granule formation
Previous studies have reported that in the absence of RNA-binding proteins G3BP1/G3BP2 cells do not form SG as they are essential proteins serving as a platform for RNA-protein and protein-protein interactions. ∆∆G3BP1/2 cells treated with hippuristanol under arsenite stress partially restored SG formation. Similarly, over-expression of eIF4A inhibited SG formation under arsenite stress. Restoration of SG formation was more pronounced upon depletion of ATP levels than hippuristanol treatment as this affects other ATP-dependent RNA helicases, thus providing evidence for the involvement of other RNA helicases in addition to eIF4A.
Figure 4c from the preprint showing over-expression (OE) of eIF4A1 leads to decrease in SGs as monitored by PABPC1 immunofluorescence (green)
- eIF4A limits docking of P-bodies with SGs
The membrane-less RNP granules, like P-bodies (PB) and SGs often dock onto one another in a cell. eIF4A also regulates this docking as there was increased amount of SG/PB interface in cells treated with aresenite and hippuistanol compared to cells treated with arsenite and PatA or arsenite alone.
- eIF4A1 sufficiently reduces formation of condensates in vitro
The formation of RNA condensates is significantly reduced in the presence of cytosolic concentration of recombinant eIF4A and ATP. Thus, ATP hydrolysis, and therefore the ATP-dependent helicase activity of eIF4A alone is sufficient to reduce RNA condensation by limiting RNA-RNA interactions.
Reasons for choosing this preprint
I have an avid interest in studying RNA helicases and their modulatory mechanisms influencing various cellular processes. eIF4A, an essential human protein, has long been known as a helicase that plays a role in translation initiation. This preprint for the first time very elegantly highlights a novel function of eIF4A in limiting SG formation and thus opens up the possibility that other such helicases could be present in the cell. The sophisticated methodology employed and intelligently designed controls make it a robust study for future follow-ups.
Future directions/questions for the authors
- How are the levels of eIF4A regulated to distribute its activity between the two functions, translational initiation and helicase activity? What is the molecular switch that enables eIF4A to assume these two separable functions?
- The present study focuses only on arsenite stress, but do RNA helicases take on stress-specific roles in response to other stresses like heat- shock or serum starvation?
- Are there specific RNA sequence determinants that define specificity of this ‘decondensase’ activity?
References and further reading
- Jain, A., & Vale, R. D. (2017). RNA phase transitions in repeat expansion. Nature, 546(7657), 243–247.
- Protter, D. S. W., & Parker, R. (2016). Principles and Properties of Stress. Trends in Cell Biology, 26(9), 668–679.
doi: https://doi.org/10.1242/prelights.12740
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