Control of RNP motility and localization by a splicing-dependent structure in oskar mRNA

Ghosh, Supurna; Marchand, Virginie; Gáspár, Imre; Ephrussi, Anne

doi:10.1038/nsmb.2257

Cited by 113 publications

(180 citation statements)

References 43 publications

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“…Which activity is observed depends on the cellular context, the identity of the bound RNA and the location of the binding site on the target RNA. Many of Staufen's previously documented activities parallel those of the EJC [7][8][9][10][11]19,20,33,[35][36][37][38] . To better understand EJC function, we recently determined the complete EJC RNA-binding landscape in HEK293 cells 24 .…”

Section: Discussionmentioning

confidence: 95%

Staufen1 senses overall transcript secondary structure to regulate translation

Ricci

Küçükural

Cenik

et al. 2013

Nat Struct Mol Biol

122

184

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Human Staufen1 (Stau1) is a double-stranded RNA (dsRNA)-binding protein implicated in multiple post-transcriptional gene-regulatory processes. Here we combined RNA immunoprecipitation in tandem (RIPiT) with RNase footprinting, formaldehyde cross-linking, sonication-mediated RNA fragmentation and deep sequencing to map Staufen1-binding sites transcriptome wide. We find that Stau1 binds complex secondary structures containing multiple short helices, many of which are formed by inverted Alu elements in annotated 3′ untranslated regions (UTRs) or in 'strongly distal' 3′ UTRs. Stau1 also interacts with actively translating ribosomes and with mRNA coding sequences (CDSs) and 3′ UTRs in proportion to their GC content and propensity to form internal secondary structure. On mRNAs with high CDS GC content, higher Stau1 levels lead to greater ribosome densities, thus suggesting a general role for Stau1 in modulating translation elongation through structured CDS regions. Our results also indicate that Stau1 regulates translation of transcription-regulatory proteins.Staufen proteins are highly conserved dsRNA-binding proteins (dsRBPs) found in most bilateral animals 1 . Mammals contain two Staufen paralogs encoded by different loci. Stau1, Reprints and permissions information is available online at

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Section: Discussionmentioning

confidence: 95%

Staufen1 senses overall transcript secondary structure to regulate translation

Ricci

Küçükural

Cenik

et al. 2013

Nat Struct Mol Biol

122

184

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“…Oskar RNA is synthesized during oogenesis in the nurse cells, the sister cells of the oocyte, and transported toward the oocyte's posterior pole by a process involving the exon junction complex, the oskar 3′UTR, and microtubule-based movement (5,6). Oskar protein translation is repressed during transport by the RNA-binding protein Bruno and this repression is released by the binding of activators, such as Orb, once the RNA reaches the posterior pole (7)(8)(9)(10)(11).…”

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confidence: 99%

Structure of Drosophila Oskar reveals a novel RNA binding protein

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Oskar (Osk) protein plays critical roles during Drosophila germ cell development, yet its functions in germ-line formation and body patterning remain poorly understood. This situation contrasts sharply with the vast knowledge about the function and mechanism of osk mRNA localization. Osk is predicted to have an N-terminal LOTUS domain (Osk-N), which has been suggested to bind RNA, and a C-terminal hydrolase-like domain (Osk-C) of unknown function. Here, we report the crystal structures of Osk-N and Osk-C. Osk-N shows a homodimer of winged-helix–fold modules, but without detectable RNA-binding activity. Osk-C has a lipase-fold structure but lacks critical catalytic residues at the putative active site. Surprisingly, we found that Osk-C binds the 3′UTRs of osk and nanos mRNA in vitro. Mutational studies identified a region of Osk-C important for mRNA binding. These results suggest possible functions of Osk in the regulation of stability, regulation of translation, and localization of relevant mRNAs through direct interaction with their 3′UTRs, and provide structural insights into a novel protein–RNA interaction motif involving a hydrolase-related domain.

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“…Splicing of the first intron of the Oskar pre-mRNA generates a secondary structure that is required for precise localization of the mRNA. This stem-loop structure encompasses the exon-exon junction and creates binding sites for a variety of transacting factors (Hachet and Ephrussi 2004;Yano et al 2004;Ghosh et al 2012). It is not known if similar coupled-regulatory mechanisms exist in mammalian genomes.…”

Section: Discussionmentioning

confidence: 99%

Frac-seq reveals isoform-specific recruitment to polyribosomes

et al. 2013

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Pre-mRNA splicing is required for the accurate expression of virtually all human protein coding genes. However, splicing also plays important roles in coordinating subsequent steps of pre-mRNA processing such as polyadenylation and mRNA export. Here, we test the hypothesis that nuclear pre-mRNA processing influences the polyribosome association of alternative mRNA isoforms. By comparing isoform ratios in cytoplasmic and polyribosomal extracts, we determined that the alternative products of ∼30% (597/1954) of mRNA processing events are differentially partitioned between these subcellular fractions. Many of the events exhibiting isoform-specific polyribosome association are highly conserved across mammalian genomes, underscoring their possible biological importance. We find that differences in polyribosome association may be explained, at least in part by the observation that alternative splicing alters the cis-regulatory landscape of mRNAs isoforms. For example, inclusion or exclusion of upstream open reading frames (uORFs) in the 5′UTR as well as Alu-elements and microRNA target sites in the 3′UTR have a strong influence on polyribosome association of alternative mRNA isoforms. Taken together, our data demonstrate for the first time the potential link between alternative splicing and translational control of the resultant mRNA isoforms.

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Control of RNP motility and localization by a splicing-dependent structure in oskar mRNA

Cited by 113 publications

References 43 publications

Staufen1 senses overall transcript secondary structure to regulate translation

Staufen1 senses overall transcript secondary structure to regulate translation

Structure of Drosophila Oskar reveals a novel RNA binding protein

Frac-seq reveals isoform-specific recruitment to polyribosomes

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