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Article
| Open AccessTRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer
TGFβ can function as both a tumour suppressor and tumour promoter under different cellular contexts. Here, the cleavage product of the TGFβ type I receptor is shown to be generated in a TGFβ-dependent manner, and can induce the expression of genes involved in tumour cell invasion.
- Yabing Mu
- , Reshma Sundar
- & Marene Landström
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Article
| Open AccessCircadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus
Circadian rhythm is controlled by the suprachiasmatic nucleus and the mechanisms that control the rhythm are largely undiscovered. In this study, a G protein regulator, RGS16, is shown to be involved in the production of cyclic AMP that is required for the suprachiasmatic nucleus to maintain rhythm
- Masao Doi
- , Atsushi Ishida
- & Hitoshi Okamura
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Article
| Open AccessThe rice mitochondrial iron transporter is essential for plant growth
Increasing the nutritional content of plant crops and the identification of iron transporters in rice would facilitate the improvement of rice varieties. In this study, the authors identify a mitochondrial iron transporter in rice — MIT — and suggest that this gene is important for rice growth and development.
- Khurram Bashir
- , Yasuhiro Ishimaru
- & Naoko K. Nishizawa
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Article
| Open AccessAurora B potentiates Mps1 activation to ensure rapid checkpoint establishment at the onset of mitosis
Mitotic exit is controlled by a cell division checkpoint that prevents premature degradation of cyclin B by the anaphase-promoting complex. Saurinet al. show that Aurora B directly regulates timely establishment of this checkpoint by facilitating activation of Mps1 kinase at unattached kinetochores.
- Adrian T. Saurin
- , Maike S. van der Waal
- & Geert J.P.L. Kops
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Recovery from chronic monocular deprivation following reactivation of thalamocortical plasticity by dark exposure
Amblyopia induced by chronic monocular deprivation can be reversed by dark exposure, followed by reverse deprivation in adulthood. The authors show that dark exposure in adulthood reactivates plasticity in the visual cortex, including thalamocortical synapses, promoting recovery from deprivation amblyopia.
- Karen L. Montey
- & Elizabeth M. Quinlan
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Article
| Open AccessStructure and Scm3-mediated assembly of budding yeast centromeric nucleosomes
There is debate about the structural organization of the yeast centromeric nucleosome and the role of the nonhistone protein Scm3 in its assembly. Dechassaet al.find that yeast centromeric nucleosomes organize DNA in a left-handed superhelix, and show that Scm3 is a specific nucleosome assembly factor.
- Mekonnen Lemma Dechassa
- , Katharina Wyns
- & Karolin Luger
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Article
| Open AccessIKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways
IKK kinases activate nuclear factor-κB, and the activated form of this transcription factor is found in endothelial cells in diseased tissue. In this study, mice lacking IKKβ in the endothelium are generated, and it is shown that defects in endothelial cell function are both IKK kinase activity dependent and independent.
- Noboru Ashida
- , Sucharita SenBanerjee
- & Anthony Rosenzweig
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Engineering biosynthetic excitable tissues from unexcitable cells for electrophysiological and cell therapy studies
Patch-clamp recordings are used to study the function of ion channels, but the method does not allow the assessment of tissue-level function. Kirkton and Bursac introduce a biosynthetic system for the study of channel activity and electrical conduction, facilitating studies of ion channel function.
- Robert D. Kirkton
- & Nenad Bursac
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Article
| Open AccessRapid cell-surface prion protein conversion revealed using a novel cell system
The study of prion diseases has been hampered as there is no method to distinguish newly formed abnormal prion protein conformers. Here, the authors describe a method to study newly formed abnormal prion protein and demonstrate that it is produced within 1 minute of cell exposure to prions.
- R. Goold
- , S. Rabbanian
- & S.J. Tabrizi
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Article
| Open AccessRespiratory distress and perinatal lethality in Nedd4-2-deficient mice
In vitrostudies have suggested that the ubiquitin ligase, Nedd4-2, regulates several proteins, including the epithelial sodium channel. Here by examining Nedd4-2-deficient mice, the authors demonstrate that Nedd4-2 is essential for epithelial sodium channel regulation, fetal and postnatal lung function and animal survival.
- Natasha A. Boase
- , Grigori Y. Rychkov
- & Sharad Kumar
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Article
| Open AccessUnidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells
Exosomes released from cells can transfer RNA to recipient cells. In this study, the authors demonstrate that microRNAs in exosomes from T cells can be transferred to antigen-presenting cells during immune synapsis, and that this can alter gene expression, suggesting a new form of cellular communication.
- María Mittelbrunn
- , Cristina Gutiérrez-Vázquez
- & Francisco Sánchez-Madrid
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LTD is a protein required for sorting light-harvesting chlorophyll-binding proteins to the chloroplast SRP pathway
Chloroplast proteins are synthesized in the cytosol and imported into the chloroplast before being delivered to the thylakoids. The authors report that an ankyrin-repeat protein, LTD, is essential for the routing of chlorophyll-binding proteins to the signal recognition particle pathway.
- Min Ouyang
- , Xiaoyi Li
- & Lixin Zhang
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Article
| Open AccessNeural crest cells organize the eye via TGF-β and canonical Wnt signalling
In the developing eye, the lens and retina are derived from different embryonic tissues, and how these two structures develop next to each other is of interest. In this study, the authors show that transforming growth factor-β secreted by neural crest cells is critical for the positioning of the lens next to the retina.
- Timothy Grocott
- , Samuel Johnson
- & Andrea Streit
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Article
| Open AccessAnnexin-A5 assembled into two-dimensional arrays promotes cell membrane repair
Eukaryotic cell plasma membranes possess a mechanism to repair tears caused by stimuli such as mechanical stress. The authors demonstrate that annexin-A5, when assembled into two-dimensional arrays in the presence of calcium, is required for membrane repair.
- Anthony Bouter
- , Céline Gounou
- & Alain R. Brisson
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Article
| Open AccessThe nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells
Regulatory T cells are characterized by the expression of Foxp3, however, how the expression of this protein is controlled is unclear. Here, the authors show that the nuclear orphan receptor, Nr4a2, is a transcriptional activator of Foxp3, and suggest that it is required for the function of regulatory T cells.
- Takashi Sekiya
- , Ikkou Kashiwagi
- & Akihiko Yoshimura
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Article
| Open AccessThe deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility
Deubiquitinating enzymes are involved in multiple cellular processes, including cell viability. The authors reveal a role for the deubiquitinating enzyme, USP17, in the migration of cells in response to chemokines and show that USP17 is required for the relocalization of GTPases involved in cell motility.
- Michelle de la Vega
- , Alyson A. Kelvin
- & James A. Johnston
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Article
| Open AccessIntestinal epithelial stem cells do not protect their genome by asymmetric chromosome segregation
It has been proposed that stem cells use nonrandom chromosome segregation to avoid the accumulation of replication-induced mutations. Here, the authors examine intestinal epithelial stem cell division and show, using label exclusion and retention assays, that the cells segregate their chromosomes randomly.
- Marion Escobar
- , Pierre Nicolas
- & Catherine Legraverend
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The acetylation of tau inhibits its function and promotes pathological tau aggregation
Phosphorylation of the microtubule-associated protein tau is associated with disease, but other post-translational modifications of tau are not well studied. Here, Cohenet al. study the acetylation of tau and suggest that this form of the protein may be associated with tauopathies.
- Todd J. Cohen
- , Jing L. Guo
- & Virginia M. Y. Lee
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Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25
Sox9 is an important transcription factor in the formation of cartilage chondrogenesis that occurs during skeletal development. Nakamuraet al.show that Sox9 interacts with Wwp2 and Med25 to form a complex and that loss of either protein in zebrafish results in altered palate chondrogenesis.
- Yukio Nakamura
- , Koji Yamamoto
- & Haruhiko Akiyama
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Article
| Open AccessDrosophila neuroblasts retain the daughter centrosome
Asymmetric partitioning of centrosomes has been reported inDrosophilaneuroblasts, but whether this type of division has implications for stem cell self-renewal is unclear. In this study, the authors show that the asymmetric division of the centrosomes correlates with the asymmetric fate of the cells and that the daughter centrosome is retained by the neuroblast.
- Jens Januschke
- , Salud Llamazares
- & Cayetano Gonzalez
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Migration of growth factor-stimulated epithelial and endothelial cells depends on EGFR transactivation by ADAM17
Activation of the receptor tyrosine kinases FGFR2 and VEGFR2 results in ERK1/2 phosphorylation and cell migration. Here, the authors demonstrate that shedding of HB-EGF—a substrate of the metalloproteinase ADAM17—and activation of EGFR is required for FGFR2 and VEGFR2 mediated cell migration.
- Thorsten Maretzky
- , Astrid Evers
- & Carl P. Blobel
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A C2 domain protein kinase initiates phagocytosis in the protozoan parasite Entamoeba histolytica
The phagocytosis of bacteria and other cells by trophozoites is an important process required for nutrition and pathogenesis. The authors identify a kinase, EhC2PK, that binds to the calcium-binding protein, EhCaBP1, and find that both proteins are involved in phagocytosis by the parasiteEntamoeba histolytica.
- Somlata
- , Sudha Bhattacharya
- & Alok Bhattacharya
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Article
| Open AccessRetinoid-independent motor neurogenesis from human embryonic stem cells reveals a medial columnar ground state
There is much interest in generating motor neurons from embryonic stem cells because they may be useful for the study of neurodegenerative disease. Pataniet al. show that in the absence of retinoic acid, neurons with features of medial motor columnar neurons can be generated from human embryonic stem cells.
- R. Patani
- , A. J. Hollins
- & S. Chandran
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Article
| Open AccessGipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human
Progressive sensorineural hearing loss affects many people, but the underlying genetics remain largely undefined. Here, the authors identify mutations inGIPC3in mice and two consanguineous families that lead to hearing loss and in mice cause defects in the structure of stereocilia bundles and audiogenic seizures.
- Nikoletta Charizopoulou
- , Andrea Lelli
- & Konrad Noben-Trauth
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Article
| Open AccessC-terminal UBA domains protect ubiquitin receptors by preventing initiation of protein degradation
Rad23 and Dsk2 bind polyubiquitylated proteins and escort them to the proteasome for destruction. In this study, Heinenet al.investigate the molecular mechanisms that protect the C-terminal UBA domains of Rad23 and Dsk2 from proteasomal destruction.
- Christian Heinen
- , Klàra Ács
- & Nico P. Dantuma
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Article
| Open AccessCSN-mediated deneddylation differentially modulates Ci155 proteolysis to promote Hedgehog signalling responses
Hedgehog signalling gradients are required for proper wing formation inDrosophila, and Hedgehog is known to regulate the cubitus interruptus transcription factor. Here, the authors show that the COP9 signalosome has a critical role in translating a Hedgehog gradient into a cubitus interruptus gradient.
- June-Tai Wu
- , Wei-Hsiang Lin
- & Cheng-Ting Chien
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Article
| Open AccessDifferential use of importin-α isoforms governs cell tropism and host adaptation of influenza virus
Interspecies transmission of influenza A viruses requires adaptation of the viral polymerase to the host importin-α. Here, the polymerase subunit PB2 and the nucleoprotein of avian viruses are found to require importin-α3, whereas mammalian viruses are shown to require importin-α7.
- Gülsah Gabriel
- , Karin Klingel
- & Hans-Dieter Klenk
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Asymmetric spermatocyte division as a mechanism for controlling sex ratios
Some organisms produce unequal numbers of male and female progeny, but the mechanics of skewed of sex ratios are largely unknown. Here, the authors describe alterations in X-chromosome segregation and cytoplasmic partitioning during spermatogenesis that together explain the distorted sex ratio in a nematode species.
- Diane C. Shakes
- , Bryan J. Neva
- & Andre Pires-daSilva
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Article
| Open AccessLeucine-rich repeat kinase LRRK1 regulates endosomal trafficking of the EGF receptor
Activation of the epidermal growth factor receptor can result in its internalization and subsequent intracellular trafficking. In this study, the authors show that leucine-rich repeat kinase-1 can bind to the receptor and regulate its trafficking between different endosomal compartments.
- Hiroshi Hanafusa
- , Kouki Ishikawa
- & Kunihiro Matsumoto
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Article
| Open AccessSynthetic human cell fate regulation by protein-driven RNA switches
The control of cell fate and apoptosis is a continuing challenge in synthetic biology. In this study, systems are developed in which an intracellularly expressed genome-encoded protein simultaneously achieves up- and downregulation of two distinct apoptosis pathways.
- Hirohide Saito
- , Yoshihiko Fujita
- & Tan Inoue
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Article
| Open AccessTumour-initiating stem-like cells in human prostate cancer exhibit increased NF-κB signalling
Tumours consist of heterogeneous cell types that respond differently to treatment. Here, on the basis of the expression of three different proteins, the authors describe a subset of prostate cancer cells that have stem cell-like properties that are able to initiate tumour formationin vivo.
- Vinagolu K. Rajasekhar
- , Lorenz Studer
- & Howard I. Scher
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Article
| Open AccessNeural stem and progenitor cells shorten S-phase on commitment to neuron production
During neurogenesis, neural stem and progenitor cells can either proliferate or produce neurons. Here, the authors show that proliferating neural stem and progenitor cells have a longer S-phase portion of the cell cycle than cells committed to neuron production, suggesting that this may enable faithful DNA replication.
- Yoko Arai
- , Jeremy N. Pulvers
- & Wieland B. Huttner
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The phospholipase D1 pathway modulates macroautophagy
Macroautophagy involves remodelling of intracellular membranes, but the role of lipids and lipid enzymes in this process is poorly understood. Here, the authors demonstrate that phospholipase D1, an enzyme that catalyses the production of phosphatidic acid, has a modulatory role in the autophagy process in mammalian cells.
- Claudia Dall'Armi
- , Andrés Hurtado-Lorenzo
- & Gilbert Di Paolo
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Article
| Open AccessSystems-wide temporal proteomic profiling in glucose-starved Bacillus subtilis
Identifying the transcripts and proteins that fluctuate in response to stimuli provides important information for understanding cell physiology. In this study, 52% of theBacillus subtilispredicted proteome is identified following glucose starvation, revealing further insight into protein dynamics at a global scale.
- Andreas Otto
- , Jörg Bernhardt
- & Dörte Becher
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Cyclic hardening in bundled actin networks
Materials such as rubber tend to soften when cyclically deformed. Here, however, the authors find that bundled actin networks can show cyclic hardening and retain a memory of the maximum strain they have been subjected to.
- K. M. Schmoller
- , P. Fernández
- & A. R. Bausch
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Article
| Open AccessDisruption of TBP-2 ameliorates insulin sensitivity and secretion without affecting obesity
Thioredoxin binding protein-2 (TBP-2) mutant mice have abnormal insulin sensitivity and secretion. In this study, TBP-2-null obese mice are shown to have improved insulin sensitivity and glucose intolerance, suggesting a potential role for TBP-2 inhibition in diabetes treatment.
- Eiji Yoshihara
- , Shimpei Fujimoto
- & Hiroshi Masutani
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Overlap between folding and functional energy landscapes for adenylate kinase conformational change
Enzyme function is often dependent on fluctuations between inactive and active states. Olsson and Wolf-Watz show that switching between the inactive and active states of adenylate kinase is associated with partial unfolding/refolding of the enzyme.
- Ulrika Olsson
- & Magnus Wolf-Watz
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Article
| Open AccessA β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain
Little is known about β-synuclein mutations in neurological disease. In this article, the authors demonstrate that mice with a mutation in β-synuclein show progressive neurodegenerative disease and suggest that this mutation can enhance the brain defects caused by α-synuclein mutations in mice.
- Masayo Fujita
- , Shuei Sugama
- & Makoto Hashimoto
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G-protein β2 subunit interacts with mitofusin 1 to regulate mitochondrial fusion
Little is known about the regulation of mitofusin proteins that are involved in the fusion of mitochondrial membranes. In this study, the authors report that a heterotrimeric G protein, Gβ-subunit 2, can interact with mitofusin 1, and is involved in the regulation of mitochondrial fusion.
- Juan Zhang
- , Weihua Liu
- & Quan Chen
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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
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Article
| Open AccessFolding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone
Toll-like receptors are involved in pathogen recognition by the innate immune system and rely on the molecular chaperone, gp96, for correct folding. In this article, the chaperone activity of gp96 is shown to be dependent on an additional endoplasmic reticulum protein, CNPY3, for some Toll-like receptors.
- Bei Liu
- , Yi Yang
- & Zihai Li
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Article
| Open AccessRapid calcium-dependent activation of Aurora-A kinase
Aurora-A kinase localizes to centrosomes, is involved in the progression through mitosis and is overexpressed in certain cancers. Here, calcium is shown to induce Aurora-A auto-phosphorylation in a calmodulin-dependent manner, suggesting a novel role for Aurora-A in non-mitotic cells.
- Olga V. Plotnikova
- , Elena N. Pugacheva
- & Erica A. Golemis
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A single-vesicle content mixing assay for SNARE-mediated membrane fusion
SNARE protein-mediated vesicle fusion is usually monitored by indirect lipid mixing. Diaoet al. have developed a FRET-based single-vesicle content mixing assay, which elucidates fusion pore formation, and shows that the yeast SNARE complex mediates pore expansion in the absence of accessory proteins.
- Jiajie Diao
- , Zengliu Su
- & Taekjip Ha
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Calmodulin methyltransferase is an evolutionarily conserved enzyme that trimethylates Lys-115 in calmodulin
Calmodulin is a key mediator of calcium-dependent signalling and is subject to post-translational modifications. Here, evolutionarily conserved methyltransferases are identified which trimethylate Lys-115 of calmodulin, implying a broad role in calcium-dependent signalling.
- Roberta Magnani
- , Lynnette M.A. Dirk
- & Robert L. Houtz
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Article
| Open AccessIdentification of Thymosin β4 as an effector of Hand1-mediated vascular development
The Hand1 transcription factor plays a central role in cardiovascular development. Here the authors demonstrate that Hand1 regulates thymosin β4 and that the delivery of synthetic thymosin β4 can rescue some of the vascular defects in Hand1 null mouse embryos.
- Nicola Smart
- , Karina N. Dubé
- & Paul R. Riley
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Article
| Open AccessOuabain protects against adverse developmental programming of the kidney
Poor maternal nutrition is known to affect fetal kidney development. This study shows that the sodium potassium ATPase ligand, ouabain, protects kidneys from cell death induced by serum starvationin vitro and from abnormal kidney development due to a low-protein diet in vivo.
- Juan Li
- , Georgiy R. Khodus
- & Anita Aperia
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Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes
Pseudogenes are prevalent in the human genome; however, their biological function is relatively unknown. In this study, the high mobility group A1 (HMGA1) pseudogene is shown to destabilizeHMGA1 mRNA. These findings have implications for diabetes, as two patients are reported to express high levels of the HMGA1pseudogene.
- Eusebio Chiefari
- , Stefania Iiritano
- & Antonio Brunetti
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PI(3,5)P2 controls membrane trafficking by direct activation of mucolipin Ca2+ release channels in the endolysosome
Phosphoinositides activate intracellular ion channels to release Ca2+ from membrane-bound stores. This study demonstrates that Ca2+-permeable mucolipin TRP channels, TRPMLs, are activated by the phospholipid PI(3,5)P2in murine endolysosomes and yeast vacuoles.
- Xian-ping Dong
- , Dongbiao Shen
- & Haoxing Xu
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TERRA transcripts are bound by a complex array of RNA-binding proteins
Recent work has revealed that the TTAGGG DNA repeats of telomeres are transcribed to form 'TERRA'. In this study, a set of RNA-binding proteins are shown to bind TERRA transcripts, altering the location of these transcripts at telomeres and regulating telomere abundance and length.
- Isabel López de Silanes
- , Martina Stagno d'Alcontres
- & Maria A Blasco
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