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https://www.readbyqxmd.com/read/29331583/importins-%C3%AE-and-%C3%AE-signaling-mediates-endothelial-cell-inflammation-and-barrier-disruption
#1
Antony Leonard, Arshad Rahman, Fabeha Fazal
Nucleocytoplasmic shuttling via importins is central to the function of eukaryotic cells and an integral part of the processes that lead to many human diseases. In this study, we addressed the role of α and β importins in the mechanism of endothelial cell (EC) inflammation and permeability, important pathogenic features of many inflammatory diseases such as acute lung injury and atherosclerosis. RNAi-mediated knockdown of importin α4 or α3 each inhibited NF-κB activation, proinflammatory gene (ICAM-1, VCAM-1, and IL-6) expression, and thereby endothelial adhesivity towards HL-60 cells, upon thrombin challenge...
January 10, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29322297/nuclear-distribution-of-the-trypanosoma-cruzi-rna-pol-i-subunit-rpa31-during-growth-and-metacyclogenesis-and-characterization-of-its-nuclear-localization-signal
#2
Israel Canela-Pérez, Imelda López-Villaseñor, Ana María Cevallos, Roberto Hernández
Trypanosoma cruzi is the aetiologic agent of Chagas disease. Our research group studies ribosomal RNA (rRNA) gene transcription and nucleolus dynamics in this species of trypanosomes. RPA31 is an essential subunit of RNA polymerase I (Pol I) whose presence is apparently restricted to trypanosomes. Using fluorescent-tagged versions of this protein (TcRPA31-EGFP), we describe its nuclear distribution during growth and metacyclogenesis. Our findings indicate that TcRPA31-EGFP alters its nuclear presence from concentrated nucleolar localization in exponentially growing epimastigotes to a dispersed granular distribution in the nucleoplasm of stationary epimastigotes and metacyclic trypomastigotes...
January 10, 2018: Parasitology Research
https://www.readbyqxmd.com/read/29321677/recognition-by-host-nuclear-transport-proteins-drives-disorder-to-order-transition-in-hendra-virus-v
#3
Sarah C Atkinson, Michelle D Audsley, Kim G Lieu, Glenn A Marsh, David R Thomas, Steven M Heaton, Jason J Paxman, Kylie M Wagstaff, Ashley M Buckle, Gregory W Moseley, David A Jans, Natalie A Borg
Hendra virus (HeV) is a paramyxovirus that causes lethal disease in humans, for which no vaccine or antiviral agent is available. HeV V protein is central to pathogenesis through its ability to interact with cytoplasmic host proteins, playing key antiviral roles. Here we use immunoprecipitation, siRNA knockdown and confocal laser scanning microscopy to show that HeV V shuttles to and from the nucleus through specific host nuclear transporters. Spectroscopic and small angle X-ray scattering studies reveal HeV V undergoes a disorder-to-order transition upon binding to either importin α/β1 or exportin-1/Ran-GTP, dependent on the V N-terminus...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29316492/synapse-to-nucleus-communication-from-developmental-disorders-to-alzheimer-s-disease
#4
REVIEW
Elena Marcello, Monica Di Luca, Fabrizio Gardoni
In the last decade several synaptonuclear protein messengers including Jacob, CRTC1, AIDA-1, ProSaP2/Shank3 and RNF10 have been identified and characterized as key players for modulation of synaptic transmission and synaptic plasticity. Activation of excitatory glutamatergic synapses leads to their shuttling from the synapse to the nucleus, mostly importin-mediated, and subsequent regulation of gene transcription needed for long lasting modifications of synaptic function. Accordingly, increasing evidences show that alterations of the activity of synaptonuclear messengers are correlated to synaptic failure as observed in different synaptopathies...
January 6, 2018: Current Opinion in Neurobiology
https://www.readbyqxmd.com/read/29304174/importin-%C3%AE-1-is-required-for-nuclear-import-of-herpes-simplex-virus-proteins-and-capsid-assembly-in-fibroblasts-and-neurons
#5
Katinka Döhner, Ana Ramos-Nascimento, Dagmara Bialy, Fenja Anderson, Ana Hickford-Martinez, Franziska Rother, Thalea Koithan, Kathrin Rudolph, Anna Buch, Ute Prank, Anne Binz, Stefanie Hügel, Robert Jan Lebbink, Rob C Hoeben, Enno Hartmann, Michael Bader, Rudolf Bauerfeind, Beate Sodeik
Herpesviruses are large DNA viruses which depend on many nuclear functions, and therefore on host transport factors to ensure specific nuclear import of viral and host components. While some import cargoes bind directly to certain transport factors, most recruit importin β1 via importin α. We identified importin α1 in a small targeted siRNA screen to be important for herpes simplex virus (HSV-1) gene expression. Production of infectious virions was delayed in the absence of importin α1, but not in cells lacking importin α3 or importin α4...
January 5, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29301510/exogenous-short-term-silicon-application-regulates-macro-nutrients-endogenous-phytohormones-and-protein-expression-in-oryza-sativa-l
#6
Soo-Won Jang, Yoonha Kim, Abdul Latif Khan, Chae-In Na, In-Jung Lee
BACKGROUND: Silicon (Si) has been known to regulate plant growth; however, the underlying mechanisms of short-term exogenous Si application on the regulation of calcium (Ca) and nitrogen (N), endogenous phytohormones, and expression of essential proteins have been little understood. RESULTS: Exogenous Si application significantly increased Si content as compared to the control. Among Si treatments, 1.0 mM Si application showed increased phosphorus content as compared to other Si treatments (0...
January 4, 2018: BMC Plant Biology
https://www.readbyqxmd.com/read/29290587/rapgef5-regulates-nuclear-translocation-of-%C3%AE-catenin
#7
John N Griffin, Florencia Del Viso, Anna R Duncan, Andrew Robson, Woong Hwang, Saurabh Kulkarni, Karen J Liu, Mustafa K Khokha
Canonical Wnt signaling coordinates many critical aspects of embryonic development, while dysregulated Wnt signaling contributes to common diseases, including congenital malformations and cancer. The nuclear localization of β-catenin is the defining step in pathway activation. However, despite intensive investigation, the mechanisms regulating β-catenin nuclear transport remain undefined. In a patient with congenital heart disease and heterotaxy, a disorder of left-right patterning, we previously identified the guanine nucleotide exchange factor, RAPGEF5...
December 27, 2017: Developmental Cell
https://www.readbyqxmd.com/read/29276125/nek9-phosphorylation-defines-a-new-role-for-tpx2-in-eg5-dependent-centrosome-separation-before-nuclear-envelope-breakdown
#8
Susana Eibes, Núria Gallisà-Suñé, Miquel Rosas-Salvans, Paula Martínez-Delgado, Isabelle Vernos, Joan Roig
Centrosomes [1, 2] play a central role during spindle assembly in most animal cells [3]. In early mitosis, they organize two symmetrical microtubule arrays that upon separation define the two poles of the forming spindle. Centrosome separation is tightly regulated [4, 5], occurring through partially redundant mechanisms that rely on the action of microtubule-based dynein and kinesin motors and the actomyosin system [6]. While centrosomes can separate in prophase or in prometaphase after nuclear envelope breakdown (NEBD), prophase centrosome separation optimizes spindle assembly and minimizes the occurrence of abnormal chromosome attachments that could end in aneuploidy [7, 8]...
December 13, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/29250154/microrna-24-inhibits-the-proliferation-and-migration-of-endothelial-cells-in-patients-with-atherosclerosis-by-targeting-importin-%C3%AE-3-and-regulating-inflammatory-responses
#9
Ye Zheng, Yongxing Li, Gang Liu, Xiangqian Qi, Xufen Cao
The aim of the present study was to measure the level of microRNA (miRNA or miR)-24 in the serum of patients with atherosclerosis and to investigate the effect of miR-24 on the expression of importin-α3 and tumor necrosis factor (TNF)-α, as well as the proliferation and migration of vascular endothelial cells. A total of 30 patients with atherosclerosis admitted to hospital between January and June 2016 were enrolled in the present study; 30 healthy subjects with a similar age range were enrolled as controls...
January 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29229958/egfr-feedback-inhibition-by-ran-binding-protein-6-is-disrupted-in-cancer
#10
Barbara Oldrini, Wan-Ying Hsieh, Hediye Erdjument-Bromage, Paolo Codega, Maria Stella Carro, Alvaro Curiel-García, Carl Campos, Maryam Pourmaleki, Christian Grommes, Igor Vivanco, Daniel Rohle, Craig M Bielski, Barry S Taylor, Travis J Hollmann, Marc Rosenblum, Paul Tempst, John Blenis, Massimo Squatrito, Ingo K Mellinghoff
Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. How cancer cells co-opt this process to promote tumorigenesis remains unclear. The epidermal growth factor receptor (EGFR) plays a critical role in normal development and in human cancer. Here we describe a mechanism of EGFR regulation through the importin β family member RAN-binding protein 6 (RanBP6), a protein of hitherto unknown functions. We show that RanBP6 silencing impairs nuclear translocation of signal transducer and activator of transcription 3 (STAT3), reduces STAT3 binding to the EGFR promoter, results in transcriptional derepression of EGFR, and increased EGFR pathway output...
December 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/29215074/structural-analysis-of-the-complex-between-influenza-b-nucleoprotein-and-human-importin-%C3%AE
#11
Alice Labaronne, Sigrid Milles, Amélie Donchet, Malene Ringkjøbing Jensen, Martin Blackledge, Jean-Marie Bourhis, Rob W H Ruigrok, Thibaut Crépin
Influenza viruses are negative strand RNA viruses that replicate in the nucleus of the cell. The viral nucleoprotein (NP) is the major component of the viral ribonucleoprotein. In this paper we show that the NP of influenza B has a long N-terminal tail of 70 residues with intrinsic flexibility. This tail contains the Nuclear Location Signal (NLS). The nuclear trafficking of the viral components mobilizes cellular import factors at different stages, making these host-pathogen interactions promising targets for new therapeutics...
December 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29212662/sharing-the-load-mex67-mtr2-cofunctions-with-los1-in-primary-trna-nuclear-export
#12
Kunal Chatterjee, Shubhra Majumder, Yao Wan, Vijay Shah, Jingyan Wu, Hsiao-Yun Huang, Anita K Hopper
Eukaryotic transfer RNAs (tRNAs) are exported from the nucleus, their site of synthesis, to the cytoplasm, their site of function for protein synthesis. The evolutionarily conserved β-importin family member Los1 (Exportin-t) has been the only exporter known to execute nuclear export of newly transcribed intron-containing pre-tRNAs. Interestingly, LOS1 is unessential in all tested organisms. As tRNA nuclear export is essential, we previously interrogated the budding yeast proteome to identify candidates that function in tRNA nuclear export...
December 6, 2017: Genes & Development
https://www.readbyqxmd.com/read/29196813/sense-encoded-poly-gr-dipeptide-repeat-proteins-correlate-to-neurodegeneration-and-uniquely-co-localize-with-tdp-43-in-dendrites-of-repeat-expanded-c9orf72-amyotrophic-lateral-sclerosis
#13
Shahram Saberi, Jennifer E Stauffer, Jie Jiang, Sandra Diaz Garcia, Amy E Taylor, Derek Schulte, Takuya Ohkubo, Cheyenne L Schloffman, Marcus Maldonado, Michael Baughn, Maria J Rodriguez, Don Pizzo, Don Cleveland, John Ravits
Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (C9 ALS). The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models...
December 1, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/29175432/dna-mismatch-repair-proteins-mlh1-and-pms2-can-be-imported-to-the-nucleus-by-a-classical-nuclear-import-pathway
#14
Andrea C de Barros, Agnes A S Takeda, Thiago R Dreyer, Adrian Velazquez-Campoy, Boštjan Kobe, Marcos R M Fontes
MLH1 and PMS2 proteins form the MutLα heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans. Mutations in MMR-related proteins are associated with cancer, especially with colon cancer. The N-terminal region of MutLα comprises the N-termini of PMS2 and MLH1 and, similarly, the C-terminal region of MutLα is composed by the C-termini of PMS2 and MLH1, and the two are connected by linker region. The nuclear localization sequences (NLSs) necessary for the nuclear transport of the two proteins are found in this linker region...
November 23, 2017: Biochimie
https://www.readbyqxmd.com/read/29142102/prolines-in-the-%C3%AE-helix-confer-the-structural-flexibility-and-functional-integrity-of-importin-%C3%AE
#15
Masahiro Kumeta, Hide A Konishi, Wanzhen Zhang, Sayuri Sakagami, Shige H Yoshimura
The karyopherin family of nuclear transport receptors is composed of a long array of amphiphilic α-helices and undergoes flexible conformational changes to pass through the hydrophobic crowding barrier of the nuclear pore. Here, we focused on the characteristic enrichment of prolines in the middle of the outer α-helices of importin β. When these prolines were substituted with alanine, nuclear transport activity was reduced drastically in vivo and in vitro, and caused a severe defect in mitotic progression...
November 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29127199/the-full-length-interleukin-33-flil33-importin-5-interaction-does-not-regulate-flil33-s-nuclear-localization-but-controls-its-intracellular-degradation
#16
Andrew Clerman, Zahid Noor, Rita Fishelevich, Virginia Lockatell, Brian S Hampton, Nirav G Shah, Mariah V Salcedo, Nevins W Todd, Sergei P Atamas, Irina G Luzina
Human mature interleukin-33 (MIL33) is a member of the IL-1 family and a potent regulator of immunity through its pro-T helper cell 2 (Th2) activity. Its precursor form, full-length interleukin-33 (FLIL33), is an intranuclear protein in many cell types, including fibroblasts, and its intracellular levels can change in response to stimuli. However, the mechanisms controlling the nuclear localization of FLIL33 or its stability in cells are not understood. Here, we identified importin-5 (IPO5), a member of the importin family of nuclear transport proteins, as an intracellular binding partner of FLIL33...
November 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29120325/structural-insight-into-tpx2-stimulated-microtubule-assembly
#17
Rui Zhang, Johanna Roostalu, Thomas Surrey, Eva Nogales
During mitosis and meiosis, microtubule (MT) assembly is locally upregulated by the chromatin-dependent Ran-GTP pathway. One of its key targets is the MT-associated spindle assembly factor TPX2. The molecular mechanism of how TPX2 stimulates MT assembly remains unknown because structural information about the interaction of TPX2 with MTs is lacking. Here, we determine the cryo-electron microscopy structure of a central region of TPX2 bound to the MT surface. TPX2 uses two flexibly linked elements ('ridge' and 'wedge') in a novel interaction mode to simultaneously bind across longitudinal and lateral tubulin interfaces...
November 9, 2017: ELife
https://www.readbyqxmd.com/read/29098725/the-structure-of-the-large-regulatory-%C3%AE-subunit-of-phosphorylase-kinase-examined-by-modeling-and-hydrogen-deuterium-exchange
#18
Mary Ashley Rimmer, Owen W Nadeau, Jianyi Yang, Antonio Artigues, Yang Zhang, Gerald M Carlson
Phosphorylase kinase (PhK), a 1.3 MDa regulatory enzyme complex in the glycogenolysis cascade, has four copies each of four subunits, (αβγδ)4 , and 325 kDa of unique sequence (the mass of an αβγδ protomer). The α, β and δ subunits are regulatory, and contain allosteric activation sites that stimulate the activity of the catalytic γ subunit in response to diverse signaling molecules. Due to its size and complexity, no high resolution structures have been solved for the intact complex or its regulatory α and β subunits...
November 3, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/29054975/nuclear-transport-of-the-neurospora-crassa-nit-2-transcription-factor-is-mediated-by-importin-%C3%AE
#19
Natália E Bernardes, Agnes Alessandra S Takeda, Thiago Revers Dreyer, Fernanda B Cupertino, Stela Virgilio, Nelly Pante, Maria Célia Bertolini, Marcos R M Fontes
The Neurospora crassa NIT-2 transcription factor belongs to the GATA transcription factor family and plays a fundamental role in the regulation of nitrogen metabolism by N. crassa Because NIT-2 acts by accessing DNA inside the nucleus, understanding the nuclear import process of NIT-2 is necessary to characterize its function. Thus, in this study, NIT-2 nuclear transport was investigated using a combination of biochemical, cellular and biophysical methods. A complemented strain that produced a sfGFP-NIT-2 fusion protein was constructed, and nuclear localization assessments were made under conditions that favored protein translocation to the nucleus...
October 20, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29042532/three-dimensional-context-rather-than-nls-amino-acid-sequence-determines-importin-%C3%AE-subtype-specificity-for-rcc1
#20
Rajeshwer S Sankhala, Ravi K Lokareddy, Salma Begum, Ruth A Pumroy, Richard E Gillilan, Gino Cingolani
Active nuclear import of Ran exchange factor RCC1 is mediated by importin α3. This pathway is essential to generate a gradient of RanGTP on chromatin that directs nucleocytoplasmic transport, mitotic spindle assembly and nuclear envelope formation. Here we identify the mechanisms of importin α3 selectivity for RCC1. We find this isoform binds RCC1 with one order of magnitude higher affinity than the generic importin α1, although the two isoforms share an identical NLS-binding groove. Importin α3 uses its greater conformational flexibility to wedge the RCC1 β-propeller flanking the NLS against its lateral surface, preventing steric clashes with its Armadillo-core...
October 17, 2017: Nature Communications
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