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SIRT6 is required for maintenance of telomere position effect in human cells
Chromatin is rendered silent by epigenetic marks when in proximity to telomeres, and, in yeast, this effect requires the histone-modifying enzyme Sir2. In this study, the human Sir2 family member SIRT6 is shown to modulate the telomere position effect in human cells.
- Ruth I. Tennen
- , Dennis J. Bua
- & Katrin F. Chua
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Critical roles for EphB and ephrin-B bidirectional signalling in retinocollicular mapping
How retinoganglion cell axons project correctly to the superior colliculus is poorly understood. Here, projections are shown to require EphB1, EphB2 and ephrin-B1 to terminate in the medial superior colliculus, while ephrin-B2 is essential for the mapping of both dorsal and ventral axons.
- Sonal Thakar
- , George Chenaux
- & Mark Henkemeyer
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| Open AccessA CLASP-modulated cell edge barrier mechanism drives cell-wide cortical microtubule organization in Arabidopsis
How microtubules are organized correctly in plant cells is not well understood. Ambroseet al. use 4D imaging and computer modelling to show that sharp cell edges induce microtubule depolymerization and that the microtubule-associated protein CLASP mitigates this process to modulate array organization.
- Chris Ambrose
- , Jun F. Allard
- & Geoffrey O. Wasteneys
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| Open AccessRhythmic actomyosin-driven contractions induced by sperm entry predict mammalian embryo viability
Cytoplasmic flows—the movement of cytoplasmic material—can be detected following the fertilization of an egg by a sperm in many species. In this study, rhythmic cytoplasmic flows are shown to be induced in mice by calcium-induced cytoskeleton contractions which could be used to predict the successful outcome of fertilization.
- Anna Ajduk
- , Tagbo Ilozue
- & Magdalena Zernicka-Goetz
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Local BMP receptor activation at adherens junctions in the Drosophila germline stem cell niche
Studying the physical interaction of stem cells with their niche has previously been difficult. Using a fluorescence-based reporter, Michelet al. are able to show that bone morphogenetic protein signalling occurs between Drosophilatestes germline stem cells and their niche and is via adherens junctions.
- Marcus Michel
- , Isabel Raabe
- & Christian Bökel
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Regulation of MITF stability by the USP13 deubiquitinase
MITF is a transcription factor required for melanocyte development, which is activated in some melanomas. Zhao and colleagues show that USP13 removes ubiquitin from MITF, stabilizes MITF protein levels and enhances colony formation, suggesting that USP13 may be a therapeutic target in melanoma.
- Xiansi Zhao
- , Brian Fiske
- & David E Fisher
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Detection of focal adhesion kinase activation at membrane microdomains by fluorescence resonance energy transfer
The focal adhesion kinase has a role in cell adhesion and migration. In this study, a fluorescent resonance energy transfer biosensor is designed to monitor focal adhesion kinase activity at membrane microdomains, revealing that the mechanisms that activate focal adhesion kinase are stimulus dependent.
- Jihye Seong
- , Mingxing Ouyang
- & Yingxiao Wang
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Article
| Open AccessFunctional and molecular interactions between ERK and CHK2 in diffuse large B-cell lymphoma
Chk2 is a kinase that is a potential chemotherapeutic target. Here, Chk2 and the kinase ERK are shown to functionally interact, and are elevated in expression in human diffuse B-cell lymphomas. Combinatorial inhibition of the kinases was also shown to block tumour growth in anin vivomouse model.
- Bojie Dai
- , X. Frank Zhao
- & Ronald B. Gartenhaus
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TorsinA participates in endoplasmic reticulum-associated degradation
The torsinA protein localizes to the endoplasmic reticulum and, when mutated, causes early onset torsion dystonia. The authors reveal a new role for torsinA in proteosome-mediated degradation of misfolded proteins, and relate this to endoplasmic reticulum stress, in aCaenorhabditis elegansmodel and patient fibroblasts.
- Flávia C. Nery
- , Ioanna A. Armata
- & Xandra O. Breakefield
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A photoconvertible fluorescent reporter to track chaperone-mediated autophagy
Soluble cytosolic proteins can be degraded in lysosomes by chaperone-mediated autophagy, however, the current method to measure this process requires isolation of lysosomes. Now, a fluorescent reporter is described that can measure this type of autophagy in intact cells.
- Hiroshi Koga
- , Marta Martinez-Vicente
- & Ana Maria Cuervo
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The Wnt3a/β-catenin target gene Mesogenin1 controls the segmentation clock by activating a Notch signalling program
During development, Wnt-mediated Notch signalling controls the generation of somites from the presomitic mesoderm, but the precise signalling mechanism is unknown. Here, the transcription factor Mesogenin 1 is shown to be a direct target of Wnt3a and regulates the transcription of a Notch signalling program.
- Ravindra B. Chalamalasetty
- , William C. Dunty Jr
- & Terry P. Yamaguchi
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| Open AccessCalcium modulates force sensing by the von Willebrand factor A2 domain
von Willebrand factor (VWF) multimers mediate primary adhesion and aggregation of platelets. Jakobiet al. reveal a calcium-binding site in the VWF-A2 domain, and show that calcium binding encourages folding of the protein and has a role in mechanosensing.
- Arjen J. Jakobi
- , Alireza Mashaghi
- & Eric G. Huizinga
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TRPV3 regulates nitric oxide synthase-independent nitric oxide synthesis in the skin
Nitric oxide can be produced by nitric oxide synthase or by nitrite reduction, but whether the latter occurs inside cells is unknown. Here, the TRPV3 ion channel is shown to induce nitrite-dependent nitric oxide production in keratinocytes, where it has a role in thermosensory behaviour and wound healing.
- Takashi Miyamoto
- , Matt J. Petrus
- & Ardem Patapoutian
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Cyclin B-dependent kinase 1 regulates human TRF1 to modulate the resolution of sister telomeres
TRF1 is a telomere binding protein involved in sister telomere cohesion. In this study, the ability of TRF1 to bind to telomeres in mitosis is inhibited by cyclin-dependent kinase 1-mediated phosphorylation, which may facilitate sister telomere resolution during mitosis.
- Megan McKerlie
- & Xu-Dong Zhu
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Article
| Open AccessRequirement of calcium-activated chloride channels in the activation of mouse vomeronasal neurons
The vomeronasal organ detects pheromones, which are thought to activate TRPC2 channels on the surface of vomeronasal neurons. Using TRPC2 knockout mice, the authors show that urinary pheromones can also activate these neurons via calcium-activated chloride channels, suggesting a TRPC2-independent pathway for sensing pheromones.
- SangSeong Kim
- , Limei Ma
- & C. Ron Yu
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Sas-4 provides a scaffold for cytoplasmic complexes and tethers them in a centrosome
Cell division and cilium formation are dependent on centrosomes that consist of two centrioles and pericentriolar material (PCM). In this study, the Sas-4 protein is shown to be important in mediating the formation of cytoplasmic PCM complexes and the incorporation of this material into centrosomes.
- Jayachandran Gopalakrishnan
- , Vito Mennella
- & Tomer Avidor-Reiss
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| Open AccessNeural coding in a single sensory neuron controlling opposite seeking behaviours in Caenorhabditis elegans
The neuronal mechanisms responsible for thermal seeking behaviour inCaenorhabditis. elegansare not fully understood. In this study, the sensory neuron AFD is shown to be involved in the responses to both cold and warm temperatures by transmitting inhibitory and excitatory signals to the interneuron AIY.
- Atsushi Kuhara
- , Noriyuki Ohnishi
- & Ikue Mori
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Atomistic mechanism for the activation and desensitization of an AMPA-subtype glutamate receptor
Upon agonist binding, ionotropic glutamate receptors are activated and then become desensitized, but the detailed molecular events of this process are unclear. Here, molecular dynamics simulations are used to probe how conformational changes of the ligand-binding domain are transmitted to the transmembrane domain.
- Hao Dong
- & Huan-Xiang Zhou
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MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma
α-fetoprotein is used as a biomarker of hepatocellular cancer but the mechanisms that lead to its elevated expression are unknown. Kojimaet al.show that microRNA122 and CUX1 are important for the regulation of α-fetoprotein and suggest that loss of microRNA122 leads to more aggressive liver cancer.
- Kentaro Kojima
- , Akemi Takata
- & Kazuhiko Koike
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Article
| Open AccessGenetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis
Complex diseases such as multiple sclerosis have both genetic and environmental components. This study demonstrates that variants of genes implicated in multiple sclerosis, and alterations in cellular metabolism and vitamin D3 levels, alterN-glycosylation, a post-translational modification causal of the disease in mice.
- Haik Mkhikian
- , Ani Grigorian
- & Michael Demetriou
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| 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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| 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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| 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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| 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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| 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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| 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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| 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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| 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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| 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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| 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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| 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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| 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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