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| Open AccessSNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation
SNURPORTIN-1, encoded by the SNUPN gene, plays a key role in the nuclear import of spliceosomal small nuclear ribonucleoproteins, however its physiological function remains unclear. Here the authors report that recessive SNUPN mutations cause a distinct subtype of childhood muscular dystrophy and reveal SNURPORTIN-1’s role in muscle homeostasis, offering insights for new therapeutic strategies.
- Marwan Nashabat
- , Nasrinsadat Nabavizadeh
- & Nathalie Escande-Beillard
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Article
| Open AccessStructural differences between the closely related RNA helicases, UAP56 and URH49, fashion distinct functional apo-complexes
UAP56 is an important factor in the TREX complex, which is responsible for mRNA export. Here the authors show that the closely related RNA helicases, UAP56 and URH49, exhibit different three-dimensional structures due to one amino acid change. Accordingly, they form distinct apo-complexes and function in the nuclear export of specific target mRNAs.
- Ken-ichi Fujita
- , Misa Ito
- & Seiji Masuda
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Article
| Open AccessThe master energy homeostasis regulator PGC-1α exhibits an mRNA nuclear export function
PGC-1α is a master regulator activating the transcription of key genes controlling the cell’s energy production. Here the authors show that PGC-1α has a function in the NXF1-dependent nuclear export of mRNAs.
- Simeon R. Mihaylov
- , Lydia M. Castelli
- & Guillaume M. Hautbergue
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Article
| Open AccessCytosolic Ptbp2 modulates axon growth in motoneurons through axonal localization and translation of Hnrnpr
The neuronal RNA-binding protein Ptbp2 is known to regulate neuronal differentiation by modulating alternative splicing. Here, the authors reveal an additional role of cytosolic Ptbp2, which regulates axon growth by fine-tuning the mRNA transport and local synthesis of an RNA-binding protein hnRNP R.
- Saeede Salehi
- , Abdolhossein Zare
- & Michael Sendtner
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Article
| Open AccessMuscleblind-like proteins use modular domains to localize RNAs by riding kinesins and docking to membranes
RNA localization is mediated by kinesin motors and anchoring. However, mechanisms underlying specificity are unclear. Here, the authors find that MBNL protein’s zinc fingers prefer specific kinesins, and its unstructured tail mediates membrane anchoring.
- Ryan P. Hildebrandt
- , Kathryn R. Moss
- & Eric T. Wang
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Article
| Open AccessInfluenza virus mRNAs encode determinants for nuclear export via the cellular TREX-2 complex
Here, Bhat et al. show that Influenza A virus mRNAs are exported from the nucleus via the nucleoporin Tpr and the mRNA export complex TREX-2. These mRNAs have low exon number, high mean exon length, and low GC content. A 45-nucleotide RNA signal can mediate export via TREX-2.
- Prasanna Bhat
- , Vasilisa Aksenova
- & Beatriz M. A. Fontoura
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Article
| Open AccessKinetics of mRNA nuclear export regulate innate immune response gene expression
The UCLA Ribonomics group reports that the nuclear export efficiency of innate immune mRNAs varies over a hundred-fold range such that for many genes only a small fraction of the newly synthesized premRNA reaches the cytoplasm. They show that nuclear export and cytoplasmic decay rates are correlated thereby ensuring similar expression levels of short-lived and long-lived mRNAs.
- Diane Lefaudeux
- , Supriya Sen
- & Sri Kosuri
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Article
| Open AccessSubcellular spatial transcriptomics identifies three mechanistically different classes of localizing RNAs
In this study the authors identify localized RNAs in the Drosophila follicular epithelium by spatial transcriptomics and through genetic analyses determine canonical and translation-based mechanisms underlying basal and apical RNA localization.
- Lucia Cassella
- & Anne Ephrussi
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Article
| Open AccessTermination of the unfolded protein response is guided by ER stress-induced HAC1 mRNA nuclear retention
Chromatin remodeler Isw1 prevents export of maturing ribonucleoprotein particles. Here, the authors show that Isw1 inhibits the Unfolded Protein Response (UPR) from the nucleus by binding and restricting export of the mRNA encoding the main effector of UPR, thereby tuning adaptation to ER stress.
- Laura Matabishi-Bibi
- , Drice Challal
- & Anna Babour
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Article
| Open AccessRNA export through the nuclear pore complex is directional
There is little information on export directionality of RNA passing through the nuclear pore complex in human cells. Here, the authors examine single RNA molecules in transit, to demonstrate 5’-first directionality for the export of mRNA and lncRNA.
- Asaf Ashkenazy-Titelman
- , Mohammad Khaled Atrash
- & Yaron Shav-Tal
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Article
| Open AccessExportin 4 depletion leads to nuclear accumulation of a subset of circular RNAs
This study identifies the evolutionarily conserved Exportin 4 as an essential regulator in the nuclear export of circRNAs. Defective circRNA export results in R-loop formation and DNA damage in cells, as well as testis and neurological defects in mice.
- Liang Chen
- , Yucong Wang
- & Ge Shan
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Article
| Open AccessRNP components condense into repressive RNP granules in the aging brain
Aberrant RNA condensates are a hallmark of age-related neurodegenerative diseases. Here, the authors show that RNA condensation increases in aging Drosophila brains, triggering translation repression.
- Kavya Vinayan Pushpalatha
- , Mathilde Solyga
- & Florence Besse
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Article
| Open AccessRNA supply drives physiological granule assembly in neurons
RNA granules are important regulators of RNA metabolism. Here the authors report that RNA granules containing RNA helicase DDX6 disassemble during neuronal maturation.
- Karl E. Bauer
- , Niklas Bargenda
- & Michael A. Kiebler
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| Open AccessContext-specific effects of sequence elements on subcellular localization of linear and circular RNAs
Ron and Ulitsky found using massively parallel assays that the effects of short RNA sequences on the subcellular localization of their host RNAs are strongly dependent on the host RNA form, linear or circular, and spliced or unspliced.
- Maya Ron
- & Igor Ulitsky
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Article
| Open AccessClueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria
Drp1 is the master regulator of mitochondrial fission, which has important impact on cellular functions. Here, Yang et al identified evolutionarily conserved proteins Clueless and its homolog CLUH as key regulators of Drp1 that function via translation of Drp1 receptors MiD49 and Mff.
- Huan Yang
- , Caroline Sibilla
- & Ming Guo
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Article
| Open AccessCanonical WNT signaling-dependent gating of MYC requires a noncanonical CTCF function at a distal binding site
Gene-gating of a MYC oncogenic super-enhancer (OSE) increases its expression in colon cancer cells in a poorly understood process. Here the authors show that MYC gating requires a CTCF binding site (CTCFBS) within the OSE that directs the stepwise trafficking of the OSE to the nuclear pore to facilitate increased nuclear export of MYC mRNA, which results in a growth advantage.
- Ilyas Chachoua
- , Ilias Tzelepis
- & Anita Göndör
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Article
| Open AccessNuclear export of the pre-60S ribosomal subunit through single nuclear pores observed in real time
Ribosomal biogenesis is known to require nuclear to cytoplasmic export, but the precise kinetics remain unclear. Here, the authors use super-resolution confocal microscopy and single molecule tracking to visualize export of single pre-60S particles through nuclear pore complexes.
- Jan Andreas Ruland
- , Annika Marie Krüger
- & Ulrich Kubitscheck
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Article
| Open AccessMicrotubule-based transport is essential to distribute RNA and nascent protein in skeletal muscle
It is increasingly recognised that the spatial localisation of RNA is important for proper cellular function. Here, the authors investigate RNA localisation in skeletal muscle and develop methods to show that global active transport of RNA is required to maintain dispersion of gene products in the large muscle syncytium.
- Lance T. Denes
- , Chase P. Kelley
- & Eric T. Wang
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| Open AccessMicrotubules orchestrate local translation to enable cardiac growth
New contractile units are required during cardiac hypertrophy, though it remains unclear precisely where and how these new sarcomeres are added. Here the authors reveal that in the heart, microtubules spatiotemporally regulate mRNAs and ribosomes to build new sarcomeres, a role which is essential for growth.
- Emily A. Scarborough
- , Keita Uchida
- & Benjamin L. Prosser
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| Open AccessExon junction complex dependent mRNA localization is linked to centrosome organization during ciliogenesis
Exon junction complexes (EJCs) that mark untranslated mRNA are involved in transport, translation and nonsense-mediated mRNA decay. Here the authors show centrosomal localization of EJCs which appears to be required for both the localization of NIN mRNA around centrosomes and ciliogenesis.
- Oh Sung Kwon
- , Rahul Mishra
- & Hervé Le Hir
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Article
| Open AccessNucleoporin TPR is an integral component of the TREX-2 mRNA export pathway
mRNAs export from the nucleus is thought to be regulated in part by three nucleoporins that comprise the nuclear basket, but whether and how distinct basket nucleoporins interact with the RNA export machinery is unclear. Here, the authors use rapid auxin-mediated degradation of basket nucleoporins Nup153, Nup50, and Tpr, and see that Tpr interacts with the TREX-2 mRNA export complex.
- Vasilisa Aksenova
- , Alexandra Smith
- & Mary Dasso
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Article
| Open AccessLive cell imaging of single RNA molecules with fluorogenic Mango II arrays
Fluorogenic RNA aptamers have been used for RNA imaging, but folding and fluorescence stability often limited their use in high resolution applications. Here the authors present an array of stably folding Mango II aptamers for imaging of coding and non-coding RNAs at single-molecule resolution, in both live and fixed cells.
- Adam D. Cawte
- , Peter J. Unrau
- & David S. Rueda
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Article
| Open AccessLive cell imaging reveals 3′-UTR dependent mRNA sorting to synapses
Asymmetric subcellular mRNA distribution is important for local translation of neuronal mRNAs. Here the authors employed MS2 live-cell imaging and showed that the reporter mRNA containing the 3’ UTR of Rgs4 shows an anterograde transport bias, dependent on neuronal activity and the protein Staufen2, and mediates sustained mRNA recruitment to synapses.
- Karl E. Bauer
- , Inmaculada Segura
- & Michael A. Kiebler
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Article
| Open AccessThe prion-like domain of Drosophila Imp promotes axonal transport of RNP granules in vivo
The physiological role of prion-like domains (PLDs) within RNA-binding proteins is not well understood. Here, authors show in Drosophila that the PLD in the protein Imp is required for localization of ribonucleoprotein granules to axons and axonal remodelling.
- Jeshlee Vijayakumar
- , Charlène Perrois
- & Florence Besse
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Article
| Open AccessSAGA DUBm-mediated surveillance regulates prompt export of stress-inducible transcripts for proteostasis
Stress-inducible transcripts are quickly exported to preserve cell survival when cells are under stress. Here, the authors suggest that Sgf73p of the SAGA deubiquitylating module monitors messenger ribonucleoprotein biogenesis to regulate non-canonical export of stress-inducible transcripts.
- Minhoo Kim
- , Yoonjung Choi
- & Daeyoup Lee
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Article
| Open AccessThe path of pre-ribosomes through the nuclear pore complex revealed by electron tomography
Large protein complexes and ribonucleoprotein particles (RNPs) such as pre-ribosomes are transported from the nucleus to the cytoplasm through the nuclear pore complex (NPC). Here the authors use ultrafast freezing and electron tomography to catch snapshots of native RNPs crossing the NPC and estimate their transit time using a probabilistic model.
- Franck Delavoie
- , Vanessa Soldan
- & Pierre-Emmanuel Gleizes
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Article
| Open AccessStructural and functional analysis of mRNA export regulation by the nuclear pore complex
The export of mRNA to the cytosol depends on the nuclear pore complex (NPC) and the activation of the helicase DDX19, but their interplay in humans remains poorly understood. Here, the authors present a structural and functional analysis of DDX19 activation, revealing how the human NPC regulates mRNA export.
- Daniel H. Lin
- , Ana R. Correia
- & André Hoelz
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| Open AccessExtracellular matrix stiffness and cell contractility control RNA localization to promote cell migration
Adenomatous polyposis coli (APC) regulates the localization of some mRNAs at cellular protrusions but the underlying mechanisms and functional roles are not known. Here the authors show that APC-dependent RNAs are enriched in contractile protrusions, via detyrosinated microtubules, and enhance cell migration.
- Tianhong Wang
- , Susan Hamilla
- & Stavroula Mili
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Article
| Open AccessRNA localization is a key determinant of neurite-enriched proteome
Subcellular localization of RNAs and proteins is important for polarized cells such as neurons. Here the authors differentiate mouse embryonic stem cells into neurons, and analyze the local transcriptome, proteome, and translated transcriptome in their cell bodies and neurites, providing a unique resource for future studies on neuronal polarity.
- Alessandra Zappulo
- , David van den Bruck
- & Marina Chekulaeva
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| Open AccessNovel RNA- and FMRP-binding protein TRF2-S regulates axonal mRNA transport and presynaptic plasticity
The molecular mechanisms regulating axonal mRNA transport are only partially understood. Here, Zhang et al. show a nontelomeric TRF2 splice variant interacts with FMRP to regulate the transport of several axonal mRNAs involved in axonal elongation and neurotransmitter release.
- Peisu Zhang
- , Kotb Abdelmohsen
- & Mark P. Mattson
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| Open AccessmRNA export through an additional cap-binding complex consisting of NCBP1 and NCBP3
The processing of RNAs transcribed by RNA polymerase II requires a cap-binding complex (CBC), consisting of NCBP1 and NCBP2. Here, the authors report an alternative CBC formed by NCBP1 and a previously uncharacterized protein, NCBP3 that is critical for RNA processing under cellular stress conditions.
- Anna Gebhardt
- , Matthias Habjan
- & Andreas Pichlmair
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Article
| Open AccessRNA export factor Ddx19 is required for nuclear import of the SRF coactivator MKL1
Nuclear import of transcriptional regulators and export of mRNA are essential steps for the manufacture of proteins in the cytoplasm. Here, Rajakylä et al.link these two activities by showing that the mRNA export factor Ddx19 promotes the nuclear import of the transcriptional coactivator MKL1.
- Eeva Kaisa Rajakylä
- , Tiina Viita
- & Maria K. Vartiainen
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Separation of a functional deubiquitylating module from the SAGA complex by the proteasome regulatory particle
The SAGA transcriptional coactivator is modulated by the 19S proteasome to increase the interaction of SAGA with transcription activators. Here, Limet al.show that the 19S proteasome mediates dissociation of a submodule of the SAGA complex in a non-proteolytic manner, which is implicated in mRNA export in yeast.
- Sungsu Lim
- , Jaechan Kwak
- & Daeyoup Lee
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High-resolution three-dimensional mapping of mRNA export through the nuclear pore
Messenger RNAs and their associated proteins are transported from the nucleus through highly selective nuclear pore complexes. Using ultrahigh resolution single-molecule imaging, the authors visualise the path taken by each messenger RNA as it negotiates the pore’s selectivity filter.
- Jiong Ma
- , Zhen Liu
- & Weidong Yang
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TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export
The TREX complex and Nxf1 are involved in the export of mRNA from the nucleus but the precise molecular function of TREX is unclear. Here, the TREX components Aly and Thoc5 are shown to bind to Nxf1 resulting in a change in Nxf1 conformation that permits binding to mRNA and nuclear export.
- Nicolas Viphakone
- , Guillaume M. Hautbergue
- & Stuart A. Wilson
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CPEB-mediated ZO-1 mRNA localization is required for epithelial tight-junction assembly and cell polarity
Zonal occludens and claudin form tight junctions near the apical surface of cells and are important in polarized epithelia. In this study, the translational regulatory sequence-specific RNA binding protein CPEB is shown to be required for the correct localization of zona occluden 1 mRNA in mammary epithelial cells.
- Kentaro Nagaoka
- , Tsuyoshi Udagawa
- & Joel D. Richter
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A role for TREX components in the release of spliced mRNA from nuclear speckle domains
The pre-mRNA splicing and TREX mRNA export machineries are found in nuclear speckle domains. Diaset al. microinject CMV-DNA constructs into cells and find that transcripts containing functional splice sites accumulate in nuclear speckles and that the TREX complex is required to release the mRNA once processed.
- Anusha P. Dias
- , Kobina Dufu
- & Robin Reed