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Translationally inhibited mRNAs control cell movement as untranslated sequences [Ribo-Seq]

ABSTRACT: Translation of localized mRNAs serves to regulate specific sites of protein synthesis and its functional activity, whereas translationally inhibited and untranslated mRNAs are compartmentalized for degradation or storage, with no recognized functional role. Here, however, we unexpectedly discover a group of functional, untranslated mRNA sequences that localize to integrin focal adhesions (FAs), dynamic multiprotein assemblies that govern cell movement. We show that specific mRNA sequences associate with native or mature FA functional states via messenger ribonucleoprotein (mRNP) complexes with the RNA and FA binding protein G3BP1, functioning to regulate cell migration. Mechanistically, the dimerizing propensity of the mRNA in G3BP1 mRNPs directly regulates FA protein function. Self-dimerizing mRNA sequences form large branched G3BP1 mRNPs, reducing FA protein turnover and extending adhesion lifetimes, inhibiting cell migration. In contrast, low self-dimerization promotes small more spheric G3BP1 mRNPs, facilitating FA complex dissolution and enhancing cell migration behaviors. Our findings define a previously unknown role for cytoplasmic mRNAs, challenging the notion that mRNAs are solely coding molecules and shedding light on their regulatory functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246955 | GEO | 2024/04/20

REPOSITORIES: GEO

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Translationally inhibited mRNAs control cell movement as untranslated sequences [RNA-seq]

Project description:Translation of localized mRNAs serves to regulate specific sites of protein synthesis and its functional activity, whereas translationally inhibited and untranslated mRNAs are compartmentalized for degradation or storage, with no recognized functional role. Here, however, we unexpectedly discover a group of functional, untranslated mRNA sequences that localize to integrin focal adhesions (FAs), dynamic multiprotein assemblies that govern cell movement. We show that specific mRNA sequences associate with native or mature FA functional states via messenger ribonucleoprotein (mRNP) complexes with the RNA and FA binding protein G3BP1, functioning to regulate cell migration. Mechanistically, the dimerizing propensity of the mRNA in G3BP1 mRNPs directly regulates FA protein function. Self-dimerizing mRNA sequences form large branched G3BP1 mRNPs, reducing FA protein turnover and extending adhesion lifetimes, inhibiting cell migration. In contrast, low self-dimerization promotes small more spheric G3BP1 mRNPs, facilitating FA complex dissolution and enhancing cell migration behaviors. Our findings define a previously unknown role for cytoplasmic mRNAs, challenging the notion that mRNAs are solely coding molecules and shedding light on their regulatory functions.

2024-04-20 | GSE246499 | GEO

ECT2 and AURKB Modulate Formation of Stress Granules Containing Transcripts from Diverse Cellular Pathways in Astrocytoma Cells

Project description:Stress granules are small RNA-protein granules that modify the translational landscape during cellular stress to promote survival. The RhoGTPase RhoA is implicated in the formation of RNA stress granules. Our data demonstrate that the cytokinetic proteins ECT2 and AurkB are localized to stress granules in human astrocytoma cells. AurkB and its downstream target histone-3 are phosphorylated during arsenite-induced stress. Chemical (AZD1152-HQPA) and siRNA inhibition of AurkB results in fewer and smaller stress granules when analyzed utilizing high throughput fluorescent based cellomics assays. RNA immunoprecipitation with the known stress granule aggregates TIAR and G3BP1 was performed on astrocytoma cells and subsequent analysis revealed that astrocytoma stress granules harbour unique mRNAs for various cellular pathways including cellular migration, metabolism, translation and transcriptional regulation. Human astrocytoma cell stress granules contain mRNA that are known to be involved in glioma signaling and the mTOR pathway. These data provide evidence that RNA stress granules are a novel form of epigenetic regulation in astrocytoma cells, which may be targetable by chemical inhibitors and enhance astrocytoma susceptiblity to conventional therapy such as radiation and chemotherapy. Astrocytoma cells were either untreated or treated with arsenite to induce stress granule formation and RNA immunoprecipitates were analyzed by exon array analysis. RNA species that were enriched in TIAR RIPs and G3BP1 RIPS, respectively were compared to compared to TIAR and G3BP1 RIPs from untreated cells and input controls. Ingenuity pathway analysis was performed on the stress granule enriched mRNAs from the TIAR and G3BP1 RIPs to identify significant functional biology networks.

2016-02-29 | E-GEOD-76814 | biostudies-arrayexpress

Composition of Staufen2 ribonucleoprotein particles in neurons

Project description:In neurons, many mRNAs are transported along neuronal dendrites to their site of translation by ribonucleoprotein complexes (mRNPs). Numerous mRNA-binding, motor and regulatory proteins within mRNPs finely regulate the fate of each of these mRNAs and their specific combination is likely to define different types of mRNA complexes and their neuronal functions. Staufen2 is a well known mRNA-binding protein present in distinct population of mRNPs in neurons and is implicated in the transport of mRNAs along the dendritic microtubules. However, little is known about the associated mRNAs in Staufen2 neuronal mRNPs complexes. As a means to understand its role in neuronal processes, a genome wide approach has been used to identify mRNAs that are co-immunoprecipitated with Staufen2 complexes from embryonic rat brains. The genome wide approach identified 1780 mRNAs associated with Staufen2 mRNPs that code for proteins involved in cellular processes such as post-translational protein modifications, RNA metabolism, intracellular transport and translation. All these mRNAs are consistent with the role of Staufen2 in synaptogenesis.

2010-07-06 | GSE16437 | GEO

G3BP1-linked mRNA partitioning supports selective protein synthesis in response to oxidative stress

Project description:Cells limit energy-consuming mRNA translation during stress to maintain metabolic homeostasis. Sequestration of mRNAs by RNA binding proteins (RBPs) into stress granules (SGs) reduces translation, but it remains unclear whether SGs also function in partitioning of specific transcripts to polysomes (PSs) to guide selective translation and stress-adaptation in cancer. Transcripts enriched in PSs, defined by polysome fractionation and RNAseq, were compared with mRNAs complexed with the SG-nucleator protein, G3BP1, defined by spatially-restricted enzymatic tagging. Short-term oxidative stress profoundly altered mRNA translation by promoting selective enrichment of transcripts within SGs or PSs. G3BP1 participates in this compartmentalisation by sequestering transcripts in SGs. Under stress, G3BP1-bound transcripts are PS-depleted and encode proteins involved in mRNA translation, pro-apoptosis, and mitochondrial function. In contrast, specific PS-enriched transcripts disassociate from G3BP1 under stress to encode proteins involved in diverse cellular cytoprotective pathways. Therefore, G3BP1 partitioning guides selective translation to support stress adaptation and cell survival.

2020-04-30 | PXD015491 | Pride

β-actin RNA-BioID

Project description:Function and fate of mRNAs is controlled by RNA binding proteins (RBPs) but determining the proteome of a specific mRNA in vivo is still challenging. RNA proximity biotinylation on the transported β-actin mRNA tagged with MS2 aptamers (RNA-BioID) is used to characterize the dynamic proteome of the β-actin mRNP in mouse embryonic fibroblasts (MEFs). We have identified > 60 β-actin associated RBPs including all six previously known as well as novel interactors. By investigating the dynamics of the β-actin mRNP in MEFs, we expand the set of β-actin mRNA associated RBPs and characterize the changes of the interacting proteome upon serum-induced mRNA localization. We report that the KH-domain containing protein FUBP3 represents a new β-actin associated RBP that binds to its 3’-untranslated region outside the known RNA localization element but is required for β-actin RNA localization. RNA-BioID will allow to obtain a dynamic view on the composition of endogenous mRNPs.

2020-03-12 | PXD010694 | Pride

G3BP1-linked mRNA partitioning supports selective protein synthesis in response to oxidative stress

2019-11-01 | GSE138058 | GEO

The DEAD-box RNA helicase PfDOZI imposes opposing actions on RNA metabolism in Plasmodium falciparum

Project description:In malaria parasites, the regulation of mRNA translation, storage and degradation during development and life stage transitions remains largely unknown. Here, we functionally characterized the DEAD-box RNA helicase PfDOZI in P. falciparum. Disruption of pfdozi enhanced asexual proliferation but reduced sexual commitment and impaired gametocyte development. By quantitative transcriptomics, we show that PfDOZI is involved in the regulation of invasion-related genes and sexual stage-specific genes during different developmental stages. PfDOZI predominantly participates in processing body-like mRNPs in schizonts but germ cell granule-like mRNPs in gametocytes to impose opposing actions of degradation and protection on different mRNA targets. We further show the formation of stress granule-like mRNPs during nutritional deprivation, highlighting an essential role of PfDOZI-associated mRNPs in stress response. Here, we demonstrate that PfDOZI participates in distinct mRNPs to maintain mRNA homeostasis in response to life-stage transition and environmental changes by differentially executing post-transcriptional regulation on the target mRNAs.

2024-04-30 | PXD051782 | Pride

SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and interacts directly with mRNAs to impair host stress response (RNA-Seq)

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein is highly expressed upon infection and is essential for viral replication, making it a promising target for antiviral drug and vaccine development. Here, starting from a functional proteomics workflow, we catalogued the protein-protein interactions of 28 SARS-CoV-2 proteins in HEK293 cells, including an evolutionarily conserved specific interaction of N with the stress granule resident proteins G3BP1 and G3BP2. N protein localizes to stress granules and sequesters G3BP1 and G3BP2 away from their normal interaction partners, thus attenuating stress granule formation. N also binds directly to host mRNAs, with a preference for 3´ UTRs, and modulates target mRNA stability. We show that SARS-CoV-2 N protein rewires the G3BP1 mRNA-binding profile, thereby suppressing host gene expression changes induced in response to cellular stress.

2021-12-17 | GSE171009 | GEO

SARS-CoV-2 Nucleocapsid protein attenuates stress granule formation and interacts directly with mRNAs to impair host stress response (iCLIP-Seq)

2021-12-17 | GSE171008 | GEO

Virtual northern on human brain samples using DNA microarrays for systematic genome wide analysis of mRNA lengths

Project description:Background We applied the Virtual Northern technique to human brain mRNA to systematically measure human mRNA transcript lengths on a genome-wide scale. Methodology/Principal Findings We used separation by gel electrophoresis followed by hybridization to cDNA microarrays to measure 8,774 mRNA transcript lengths representing at least 6,238 genes at high (>90%) confidence. By comparing these transcript lengths to the Refseq and H-Invitational full-length cDNA databases, we found that nearly half of our measurements appeared to represent novel transcript variants. Comparison of length measurements determined by hybridization to different cDNAs derived from the same gene identified clones that potentially correspond to alternative transcript variants. We observed a close linear relationship between ORF and mRNA lengths in human mRNAs, identical in form to the relationship we had previously identified in yeast. Some functional classes of protein are encoded by mRNAs whose untranslated regions (UTRs) tend to be longer or shorter than average; these functional classes were similar in both human and yeast. Conclusions/Significance Human transcript diversity is extensive and largely unannotated. Our length dataset can be used as a new criterion for judging the completeness of cDNAs and annotating mRNA sequences. Similar relationships between the lengths of the UTRs in human and yeast mRNAs and the functions of the proteins they encode suggest that UTR sequences serve an important regulatory role among eukaryotes.

2013-01-30 | E-SMDB-4088 | biostudies-arrayexpress

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