Recruitment of mRNAs to P granules by condensation with intrinsically-disordered proteins

Lee, Chih Yung S.; Putnam, Andrea; Lu, Tu; He, Shuai Xin; Ouyang, John Paul T.; Seydoux, Géraldine

doi:10.7554/elife.52896

Cited by 105 publications

(228 citation statements)

References 79 publications

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“…A recent publication by Lee et al corroborates our findings (Lee et al, 2020). They identified 492 P granule transcripts that precipitate with the intrinsically-disordered P granule factor MEG-3, and they found them to be of low ribosomal occupancy.…”

Section: Discussion Translational Repression Of Mrna Is Necessary Andsupporting

confidence: 91%

mRNA localization is linked to translation regulation in theCaenorhabditis elegansgerm lineage

et al. 2020

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Caenorhabditis elegans early embryos generate cell-specific transcriptomes despite lacking active transcription, thereby presenting an opportunity to study mechanisms of post-transcriptional regulatory control. We observed that some cell-specific mRNAs accumulate nonhomogenously within cells, localizing to membranes, P granules (associated with progenitor germ cells in the P lineage) and P-bodies (associated with RNA processing). The subcellular distribution of transcripts differed in their dependence on 3′UTRs and RNA binding proteins, suggesting diverse regulatory mechanisms. Notably, we found strong but imperfect correlations between low translational status and P granule localization within the progenitor germ lineage. By uncoupling translation from mRNA localization, we untangled a long-standing question: Are mRNAs directed to P granules to be translationally repressed, or do they accumulate there as a consequence of this repression? We found that translational repression preceded P granule localization and could occur independently of it. Further, disruption of translation was sufficient to send homogenously distributed mRNAs to P granules. These results implicate transcriptional repression as a means to deliver essential maternal transcripts to the progenitor germ lineage for later translation.

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Section: Discussion Translational Repression Of Mrna Is Necessary Andsupporting

confidence: 91%

mRNA localization is linked to translation regulation in theCaenorhabditis elegansgerm lineage

et al. 2020

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“…In contrast, the HRDE-1 loaded 22G-RNAs of P granule dependent piRNA targets (Supplemental Table 1) did not show phasing with ribosomes as observed due to a lack of 3 nucleotide periodicity ( Fig. 4c and d), in agreement with the fact that P granules are devoid of translating mRNAs 36,37 .…”

Section: Translating Mrnas Serve As the Template For 22g-rna Biogenesissupporting

confidence: 79%

Translation and codon usage regulate Argonaute slicer activity to trigger small RNA biogenesis

Cecere

Singh

Cornes

et al. 2020

Preprint

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In the Caenorhabditis elegans germline, thousands of mRNAs are concomitantly expressed with antisense 22G-RNAs, which are loaded into the Argonaute CSR-1. Despite their essential functions for animal fertility and embryonic development, how CSR-1 22G-RNAs are produced remains unknown. Here, we show that CSR-1 slicer activity is primarily involved in triggering the synthesis of small RNAs on the coding sequences of germline mRNAs and post-transcriptionally regulates a fraction of targets. CSR-1-cleaved mRNAs prime the RNA-dependent RNA polymerase, EGO-1, to synthesize 22G-RNAs in phase with ribosome translation in the cytoplasm, in contrast to other 22G-RNAs mostly synthesized in germ granules. Moreover, codon optimality and efficient translation antagonize CSR-1 slicing and 22G-RNAs biogenesis. We propose that codon usage differences encoded into mRNA sequences might be a conserved strategy in eukaryotes to regulate small RNA biogenesis and Argonaute targeting.

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“…The non-specific nature of recruitment of mRNAs into RNA granules would suggest that these structures and their associated proteins would bias their regulatory effects more strongly towards longer mRNA molecules, which contain more potential sites for non-specific protein-RNA and RNA-RNA interactions. Indeed, multiple groups have found that stress-induced RNA granules, as well as developmentally induced P granules, are enriched for long mRNA transcripts (Khong et al 2017;Padrón et al 2019;Lee et al 2020). Given the requirement for Fmr1 targets such as Poe/Ubr4 in the maintenance of cell homeostasis, these results are consistent with the model that Fmr1 evolved to maintain uniform translation by counteracting the inherent tendency of long mRNAs to partition into repressive RNPs under stressful conditions.…”

Section: Transcripts From Asd/id Genes Are Enriched In Stress Granulesupporting

confidence: 74%

FMRP activates the translation of large autism/intellectual disability proteins and stimulates N-end rule E3 ligase Poe/UBR4 production within puromycin-sensitive RNP particles

Greenblatt

Spradling

2020

Preprint

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Mutations in Fmr1 are the leading heritable cause of intellectual disability and autism spectrum disorder. We previously found that Fmr1 acts as a ~2-fold activator of translation of large proteins in Drosophila oocytes, in contrast to its proposed role as a repressor of translation elongation. Here, we show that genes associated with autism spectrum disorders tend to be dosage-sensitive and encode proteins that are larger than average. Reanalysis of Fmr1 KO mouse cortex ribosome profiling data demonstrates that autism-associated mRNAs encoding large proteins exhibit a concordant reduction in ribosome footprints, consistent with a general role for Fmr1 as a translational activator. We find no evidence that differential ribosomal pausing affects translational output in Fmr1-deficient Drosophila oocytes or mouse cortex. Furthermore, long Fmr1 target transcripts are preferentially enriched in stress granules upon acute stress. Our data thus identify a critical role for Fmr1 in promoting the translation of long, stress-sensitive, autism-associated mRNAs.

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Recruitment of mRNAs to P granules by condensation with intrinsically-disordered proteins

Cited by 105 publications

References 79 publications

mRNA localization is linked to translation regulation in theCaenorhabditis elegansgerm lineage

mRNA localization is linked to translation regulation in theCaenorhabditis elegansgerm lineage

Translation and codon usage regulate Argonaute slicer activity to trigger small RNA biogenesis

FMRP activates the translation of large autism/intellectual disability proteins and stimulates N-end rule E3 ligase Poe/UBR4 production within puromycin-sensitive RNP particles

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