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Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis
Activation of the liver receptor CAR and β-catenin are both involved in hepatocellular carcinoma. Here, the authors show that combined activation of both CAR and β-catenin in mice can drive uncontrolled liver growth and is sufficient for hepatocarcinogenesis.
- Bingning Dong
- , Ju-Seog Lee
- & David D. Moore
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| Open AccessUltrasensitive quantification of TAP-dependent antigen compartmentalization in scarce primary immune cell subsets
Antigenic peptides are loaded into major histocompatibility complex class I (MHC I) molecules after entering the ER via the TAP transporter. Here, Fischbach et al. develop a flow cytometry assay to monitor TAP-dependent peptide translocation that is sensitive enough to use on scarce primary cell subsets.
- Hanna Fischbach
- , Marius Döring
- & Robert Tampé
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Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming
T regulatory cells (Tregs) prevent immunopathology by inhibiting excessive T-cell activation. Here the authors show interactions between dendritic cells, Tregs and antigen-specific T cells in the lymph node during initiation of the immune response in real time by two-photon microscopy.
- Melanie P. Matheu
- , Shivashankar Othy
- & Michael D. Cahalan
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Synthetic lateral inhibition governs cell-type bifurcation with robust ratios
Cell-type diversity results from a series of binary cell fate decisions. Here, Matsuda et al.find that cells engineered with a Notch/Delta lateral inhibition circuit spontaneously bifurcate into Notch-active and Delta-positive subpopulations that are robust at the individual and population levels.
- Mitsuhiro Matsuda
- , Makito Koga
- & Miki Ebisuya
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Anoctamin 6 mediates effects essential for innate immunity downstream of P2X7 receptors in macrophages
Activation of purinergic P2X7 receptors is important for phagocytosis and bacterial killing. Here the authors show that a phospholipid scramblase, Anoctamin 6, is activated downstream of P2X7R and is a critical mediator of bacterial internalization and killing by macrophages.
- Jiraporn Ousingsawat
- , Podchanart Wanitchakool
- & Karl Kunzelmann
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MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer
Tumour cells sustain high levels of glycolysis even in presence of oxygen, which is known as the Warburg effect. Here the authors show that MnSOD contributes to the Warburg effect by increasing the levels of H2O2released from mitochondria, which sustains glycolysis by activating AMPK.
- Peter C. Hart
- , Mao Mao
- & Marcelo G. Bonini
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PYK2 sustains endosomal-derived receptor signalling and enhances epithelial-to-mesenchymal transition
Proline-rich tyrosine kinase 2 (PYK2) has been previously involved in the positive regulation of epithelial-to-mesenchymal transition (EMT); however, the mechanisms were not known. Here the authors uncover key roles of PYK2 during EGF-induced EMT in human mammary cell lines involving STAT3 and c-MET.
- Nandini Verma
- , Omer Keinan
- & Sima Lev
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Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis
Airway epithelia from cystic fibrosis patients show an exaggerated inflammatory response to P. aeruginosa. Here, Rimessi et al. show that P. aeruginosa exposure causes augmented Ca2+signalling in the absence of functional CFTR, leading to mitochondrial damage and activation of the NLRP3 inflammasome.
- Alessandro Rimessi
- , Valentino Bezzerri
- & Paolo Pinton
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HIV-1 Tat inhibits phagocytosis by preventing the recruitment of Cdc42 to the phagocytic cup
Phagocytic activity of macrophages is reduced in HIV-1-infected patients, but the reason for this is unknown. Here, the authors report that secreted Tat protein inhibits phagocytosis by binding to the phospholipid PI(4,5)P2and impairing the recruitment of small GTPase Cdc42 to the phagocytic cup.
- Solène Debaisieux
- , Simon Lachambre
- & Bruno Beaumelle
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| Open AccessCollaborative rewiring of the pluripotency network by chromatin and signalling modulating pathways
Improving the efficiency of reprogramming of somatic cells to induced pluripotent stem cells is of major interest. Here, the authors combine ascorbic acid and 2i (MAP kinase and GSK inhibitors) conditions and show increased efficiency and synchronicity in the reprogramming of fibroblasts and partially reprogrammed cells, and study epigenetic effectors and signalling pathways responsible for this effect.
- Khoa A. Tran
- , Steven A. Jackson
- & Rupa Sridharan
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| Open AccessToll-like receptor ligands sensitize B-cell receptor signalling by reducing actin-dependent spatial confinement of the receptor
Microbial pathogens can activate both innate and adaptive receptors, and integration of these signals may enhance the sensitivity of the immune response. Freeman et al. show that innate microbial cues sensitize B cells to antigen by increasing actin dynamics and reducing the actin-dependent confinement of the B-cell receptor.
- Spencer A. Freeman
- , Valentin Jaumouillé
- & Michael R. Gold
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| Open AccessAugmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5
Augmented AMP-activated protein kinase (AMPK) activity inhibits cell migration through an unknown mechanism. Here, Yan et al.show that AMPK phosphorylates the novel substrate PDZ and LIM domain 5 (Pdlim5), and that phosphomimetic Pdlim5 impairs cell migration by disrupting the Rac1-Arp2/3 signalling pathway.
- Yi Yan
- , Osamu Tsukamoto
- & Seiji Takashima
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| Open AccessEndothelial destabilization by angiopoietin-2 via integrin β1 activation
Angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) have opposing effects on vascular stability through their receptor Tie2, but there is evidence for Tie2-independent functions of Ang2. Here, Hakanpaa et al.show that Ang2 directly activates β1-integrin, leading to rearrangement of the actin cytoskeleton and decreased VE-cadherin in cell–cell junctions.
- Laura Hakanpaa
- , Tuomas Sipila
- & Pipsa Saharinen
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| Open AccessHydrophobic mismatch sorts SNARE proteins into distinct membrane domains
Clustering of proteins in the plasma membrane plays an important role in the regulation of both cellular signalling and membrane remodelling. Milovanovic et al.demonstrate that mismatch between transmembrane domain length and the lipid bilayer thickness is sufficient to drive clustering of SNARE proteins.
- Dragomir Milovanovic
- , Alf Honigmann
- & Reinhard Jahn
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The cleavage pattern of TDP-43 determines its rate of clearance and cytotoxicity
TAR DNA-binding protein of 43 kDa (TDP-43) and its C-terminal fragment of 25 kDa (CTF25) play critical roles in several neurodegenerative diseases but the cleavage site that generates CTF25 remains undetermined. Here the authors show that caspase-4 cleaves TDP-43 after Aps174 generating CTF25, and this leads to TDP-43 clearance and increased cell viability.
- Quan Li
- , Moe Yokoshi
- & Yukio Kawahara
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| Open AccessAn oncogenic role of Agrin in regulating focal adhesion integrity in hepatocellular carcinoma
The proteoglycan Agrin is known to be expressed in neurons and muscle and to bind ECM protein laminin. Here the authors report that Agrin promotes hepatocellular carcinoma by stimulating proliferation, decreasing focal adhesion, increasing invasiveness and promoting an epithelial-to-mesenchymal transition.
- Sayan Chakraborty
- , Manikandan Lakshmanan
- & Wanjin Hong
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| Open AccessTemporal and spatial regulation of translation in the mammalian oocyte via the mTOR–eIF4F pathway
Meiotic maturation of oocytes and early development of mammalian embryos is largely dependent on the translation of mRNAs stored in the oocyte. Here the authors uncover a population of mRNA retained in the oocyte nucleus whose translation is spatially and temporally regulated by the mTOR–eIF4F pathway during meiosis.
- Andrej Susor
- , Denisa Jansova
- & Michal Kubelka
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ADAM8 as a drug target in pancreatic cancer
Expression of ADAM8, a metalloprotease disintegrin, correlates with worse prognosis in pancreatic adenocarcinoma (PDAC). Here Schlomann et al. show that ADAM8 promotes PDAC invasiveness, and develop a peptide inhibitor that blocks ADAM8 function and impedes PDAC progression in mouse models.
- Uwe Schlomann
- , Garrit Koller
- & Jörg W. Bartsch
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Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence
Mast cells are tissue-resident immune cells important for clearance of parasitic worms but also mediating allergic reactions. Here Joulia et al. show that human mast cells form degranulatory synapses with antibody-targeted cells and pathogens to increase efficiency and minimize off-target effects.
- Régis Joulia
- , Nicolas Gaudenzio
- & Eric Espinosa
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ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP
Dominant mutations in the RNA-binding protein FUS/TLS cause amyotrophic lateral sclerosis (ALS), an adult-onset motor neuron degenerative disease. Here, the authors show that ALS-causative FUS/TLS mutations directly bind the SMN and U1-snRNP complexes, producing both loss and gain of function effects on RNA processing.
- Shuying Sun
- , Shuo-Chien Ling
- & Don W. Cleveland
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Herpes simplex virus enhances chemokine function through modulation of receptor trafficking and oligomerization
Herpes simplex viruses cause a variety of diseases, from cold sores to encephalitis. Here, Martinez-Martin et al. show that the viral protein gG binds to cell surface glycosaminoglycans and induces chemokine receptor clustering, enhancing chemokine function and thus modulating the immune response.
- Nadia Martinez-Martin
- , Abel Viejo-Borbolla
- & Antonio Alcamí
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| Open AccessFumarate induces redox-dependent senescence by modifying glutathione metabolism
Fumarate hydratase (FH) mutations are associated with renal cancer. Here, Zheng et al. use metabolomic and analytical chemistry approaches to reveal that fumarate accumulated due to FH loss covalently modifies intracellular glutathione, leading to oxidative stress and senescence.
- Liang Zheng
- , Simone Cardaci
- & Eyal Gottlieb
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An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction
Tim-3 is an inhibitory molecule that suppresses T-cell responses. Here the authors show that the cytokine IL-27, acting through the transcription factor NFIL3, induces Tim-3 in vivo, and that IL-27-conditioned Th1 cells have poor effector function.
- Chen Zhu
- , Kaori Sakuishi
- & Vijay K. Kuchroo
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| Open AccessGd-metallofullerenol nanomaterial as non-toxic breast cancer stem cell-specific inhibitor
A metallofullerenol nanomaterial, Gd@C82(OH)22, was shown to inhibit growth of several solid cancers in preclinical models and yet exhibit low toxicity. Herein the authors show that Gd@C82(OH)22functions as an inhibitor of breast cancer stem cell function via blocking TGF-β and HIF-1α signalling, while sparing normal tissue.
- Ying Liu
- , Chunying Chen
- & Yuliang Zhao
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| Open AccessUCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α
When stabilized, HIF-1 can activate adaptation to hypoxia and metastasis. Here the authors show that upregulation of Ubiquitin C-terminal hydrolase-L1 in human cancers promotes metastasis and correlates with poor prognosis because of its role in opposing ubiquitin-mediated degradation of HIF-1.
- Yoko Goto
- , Lihua Zeng
- & Hiroshi Harada
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| Open AccessDppa3 expression is critical for generation of fully reprogrammed iPS cells and maintenance of Dlk1-Dio3 imprinting
Reprogramming of mouse somatic cells into iPSCs often generates pre-iPSCs, low-grade iPSCs that show abnormal Dlk1-Dio3 imprinting, and fully reprogrammed, high-grade iPSCs. Here, the authors show that germ-cell marker Dppa3 enhances reprogramming kinetics, critical for the maintenance of Dlk1-Dio3 imprinting and generation of fully reprogrammed iPSCs.
- Xingbo Xu
- , Lukasz Smorag
- & D. V. Krishna Pantakani
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Autophagy enhances NFκB activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity
Immune activation must be carefully tuned to respond to infection and restrained to prevent tissue damage. Here the authors show that autophagy has a role in the immune response to Candida albicans, activating NFκB in macrophages by sequestering the NFκB inhibitor A20.
- Masashi Kanayama
- , Makoto Inoue
- & Mari L. Shinohara
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| Open AccessA proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting
Integrins are activated by many extracellular cues and respond by assembling diverse signalling complexes. Byron et al.use activation state-specific antibodies to proteomically characterize these complexes, and provide insight into integrin-dependent microtubule stabilization.
- Adam Byron
- , Janet A. Askari
- & Martin J. Humphries
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Chromatin decompaction by the nucleosomal binding protein HMGN5 impairs nuclear sturdiness
Whether heterochromatin affects the physical properties of the nucleus is not known. Here, Furusawa et al. show that chromatin decompaction decreases the sturdiness of the nucleus in cultured cells and leads to lamina disruption and cardiac abnormalities in adult mice, suggesting a structural, non-genetic function for heterochromatin.
- Takashi Furusawa
- , Mark Rochman
- & Michael Bustin
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| Open AccessMechanics of epithelial closure over non-adherent environments
Closure of epithelial gaps such as wounds is thought to involve contraction of an actomyosin ‘purse-string’. By creating non-adherent gaps to exclude contributions of adhesive protrusion, the authors find that large-scale tension, more than purse-string contraction, mediates closure.
- Sri Ram Krishna Vedula
- , Grégoire Peyret
- & Benoit Ladoux
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Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci
Alopecia areata (AA) is a common autoimmune disease with a known genetic component. Here, the authors analyse 3,253 AA patients and 7,543 healthy controls, and identify two new risk loci and disrupted immune response pathways associated with the disease.
- Regina C. Betz
- , Lynn Petukhova
- & Angela M. Christiano
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Internalization and vacuolar targeting of the brassinosteroid hormone receptor BRI1 are regulated by ubiquitination
Ubiquitination of cargo proteins regulates endocytosis in yeast and mammalian cells, however the extent to which this applies to plants is less clear. Martins et al. show that both internalization and vacuolar targetting of the Arabidopsisbrassinosteroid receptor BRI1 are regulated by ubiquitination.
- Sara Martins
- , Esther M. N. Dohmann
- & Grégory Vert
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The mitochondrial uniporter controls fight or flight heart rate increases
Animals react to threats by increasing their heart rate. Wu et al. show that mitochondrial calcium uptake via a highly selective ion channel, the mitochondrial calcium uniporter, stimulates metabolism in cardiac pacemaker cells and is essential for physiological pulse acceleration but not resting heart rate.
- Yuejin Wu
- , Tyler P. Rasmussen
- & Mark E. Anderson
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| Open AccessThe unexpected role of polyubiquitin chains in the formation of fibrillar aggregates
Ubiquitin is a stable and soluble protein, but it is commonly found in inclusion bodies in neurodegenerative disorders and cancer. Here, Morimoto et al. report that increasing ubiquitin chain length leads to the formation of amyloid-like fibrils, which are degraded by an autophagy mechanism.
- Daichi Morimoto
- , Erik Walinda
- & Masahiro Shirakawa
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| Open AccessA vlincRNA participates in senescence maintenance by relieving H2AZ-mediated repression at the INK4 locus
Senescence is associated with chromatin reorganization in heterochromatin foci. Here the authors show that VAD, a very long intergenic non-coding RNA activated by senescence, inhibits the incorporation of the repressive histone variant H2A.Z to INK4promoters in senescent cells.
- Sandra Lazorthes
- , Céline Vallot
- & Estelle Nicolas
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| Open AccessIntracellular CD24 disrupts the ARF–NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation
P53 is a tumour suppressor that is frequently mutated or downregulated in cancer. Here, Wang et al. show that CD24, a molecule frequently overexpressed in cancer, promotes p53 degradation by disrupting a regulatory ARF–MDM2 interaction, and silencing CD24 prevents the downregulation of p53.
- Lizhong Wang
- , Runhua Liu
- & Yang Liu
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Clustering of CARMA1 through SH3–GUK domain interactions is required for its activation of NF-κB signalling
Activating mutations in the NF-κB regulator CARMA1 are associated with a form of B-cell lymphoma. Hara et al. show that both physiological and oncogenic CARMA1 signalling can be inhibited by preventing its activation-induced clustering, which is mediated by its SH3 and GUK domains.
- Hiromitsu Hara
- , Tadashi Yokosuka
- & Takashi Saito
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ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning
Protein kinase NEK8 is important for cilliary function, but the mechanism by which it acts is unknown. Czarnecki et al. identify the cilliary protein ANKS6 as a target and crucial activator of NEK8 and describe the importance of this protein interaction in embryonic development and organogenesis.
- Peter G. Czarnecki
- , George C. Gabriel
- & Jagesh V. Shah
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PFKFB4 controls embryonic patterning via Akt signalling independently of glycolysis
PFKFB4 is an enzyme known to regulate glycolysis. The authors reveal a surprising new role for this protein in global patterning of dorsal ectoderm in frogs that is mediated by Akt signalling and independent of glycolysis.
- Caterina Pegoraro
- , Ana Leonor Figueiredo
- & Anne H. Monsoro-Burq
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DNase II-dependent DNA digestion is required for DNA sensing by TLR9
Discrimination between self and microbial DNA by innate receptors such as TLR9 relies on intracellular compartmentalization to increase specificity. Chan et al. show that activation of TLR9 by DNA ligands requires their processing by endolysosomal DNase II, restricting TLR9 activation to this organelle.
- Mei Po Chan
- , Masahiro Onji
- & Kensuke Miyake
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Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols
The protein frataxin has a role in iron–sulfur clusters biosynthesis that is still elusive. Here, the authors present a novel alkylation assay for the detection of persulfide, an intermediate in this process, and describe the function of frataxin in the control of persulfide transfer.
- Aubérie Parent
- , Xavier Elduque
- & Benoit D’Autréaux
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Article
| Open AccessAnnexin A2 promotes phagophore assembly by enhancing Atg16L+ vesicle biogenesis and homotypic fusion
The earliest steps in autophagy are thought to include the budding of Atg16L-containing vesicles from the plasma membrane and their homotypic fusion to form a phagophore. Morozova et al. reveal a role for the membrane curvature-inducing protein Annexin A2 in the formation and fusion of these vesicles.
- Kateryna Morozova
- , Sunandini Sidhar
- & Laura Santambrogio
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mab21-l3 regulates cell fate specification of multiciliate cells and ionocytes
The Notch signalling pathway has important roles in embryonic development. Here the authors show that an evolutionarily conserved gene, mab21-l3, is inhibited by Notch signalling and regulates specification of developing multiciliate cells and ion-transporting ionocytes in frog embryos.
- Chika Takahashi
- , Morioh Kusakabe
- & Eisuke Nishida
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A narrow window of cortical tension guides asymmetric spindle positioning in the mouse oocyte
Asymmetric spindle positioning in female mouse meiosis depends on the assembly of actin networks. Here, Chaigne et al. show by theoretical modelling and artificial manipulation of the oocyte cortex that a narrow stiffness regime is required to correctly position the spindle during meiosis I in the mouse oocyte.
- A. Chaigne
- , C. Campillo
- & M. E. Terret
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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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Host ICAMs play a role in cell invasion by Mycobacterium tuberculosis and Plasmodium falciparum
Intercellular adhesion molecules (ICAMs) participate in cellular processes such as host-pathogen interactions. Here, the authors show that ICAM-1 and ICAM-4 play roles in the invasion of macrophages and red blood cells by Mycobacterium tuberculosis and Plasmodium falciparum, respectively.
- Kuhulika Bhalla
- , Monika Chugh
- & Anand Ranganathan
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| Open AccessCytoplasmic TAF2–TAF8–TAF10 complex provides evidence for nuclear holo–TFIID assembly from preformed submodules
TFIID is an essential transcription factor complex that controls the expression of most protein-coding genes in eukaryotes. Here the authors identify and characterize a complex containing TAF2, TAF8 and TAF10, which assembles in the cytoplasm before integration into the nuclear holo–TFIID complex.
- Simon Trowitzsch
- , Cristina Viola
- & Imre Berger
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FBH1 influences DNA replication fork stability and homologous recombination through ubiquitylation of RAD51
The F-box DNA helicase 1 (FBH1) is implicated in suppression of homologous recombination (HR), but the precise mechanism is unclear. Here, the authors show that FBH1 can ubiquitylate RAD51, a central player in HR, and controls the subcellular localization of RAD51.
- Wai Kit Chu
- , Miranda J. Payne
- & Ian D. Hickson
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Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization
Kidney epithelial cells grown in 3D culture form polarized cysts in which basal membranes surround a lumen. Peng et al.show that the p110δ subunit of phosphoinositide 3-kinase contributes to the formation of these structures by influencing focal adhesion at the basal membrane.
- Juan Peng
- , Aline Awad
- & Ama Gassama-Diagne
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