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https://www.readbyqxmd.com/read/28190398/transforming-cytosolic-proteins-into-insoluble-and-membrane-toxic-forms-by-genetic-pathological-or-environmental-factors
#1
Jianxing Song
An increasing spectrum of diseases other than neurodegenerative diseases is characteristic of aggregation of specific proteins, while aggregation of a large number of non-specific proteins are associated with aging down to Escherichia coli. Triggered by disease-causing mutations and aging-associated damages, many well-folded cytosolic proteins become "completely insoluble" in vivo. As facilitated by our discovery in 2005 that "completely insoluble" proteins could be solubilized in unsalted water, we have deciphered that disease- and aging-associated factors act to eliminate the native folds of human VAPB-MSP and SOD1, as well as E...
February 9, 2017: Protein and Peptide Letters
https://www.readbyqxmd.com/read/28173107/neuronal-overexpression-of-human-vapb-slows-motor-impairment-and-neuromuscular-denervation-in-a-mouse-model-of-als
#2
Ji-Yoen Kim, Ava Jang, Rohit Reddy, Wan Hee Yoon, Joanna L Jankowsky
No abstract text is available yet for this article.
November 1, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28132811/the-er-mitochondria-tethering-complex-vapb-ptpip51-regulates-autophagy
#3
Patricia Gomez-Suaga, Sebastien Paillusson, Radu Stoica, Wendy Noble, Diane P Hanger, Christopher C J Miller
Mitochondria form close physical associations with the endoplasmic reticulum (ER) that regulate a number of physiological functions. One mechanism by which regions of ER are recruited to mitochondria involves binding of the ER protein VAPB to the mitochondrial protein PTPIP51, which act as scaffolds to tether the two organelles. Here, we show that the VAPB-PTPIP51 tethers regulate autophagy. We demonstrate that overexpression of VAPB or PTPIP51 to tighten ER-mitochondria contacts impairs, whereas small interfering RNA (siRNA)-mediated loss of VAPB or PTPIP51 to loosen contacts stimulates, autophagosome formation...
February 6, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28108526/vaps-and-acbd5-tether-peroxisomes-to-the-er-for-peroxisome-maintenance-and-lipid-homeostasis
#4
Rong Hua, Derrick Cheng, Étienne Coyaud, Spencer Freeman, Erminia Di Pietro, Yuqing Wang, Adriano Vissa, Christopher M Yip, Gregory D Fairn, Nancy Braverman, John H Brumell, William S Trimble, Brian Raught, Peter K Kim
Lipid exchange between the endoplasmic reticulum (ER) and peroxisomes is necessary for the synthesis and catabolism of lipids, the trafficking of cholesterol, and peroxisome biogenesis in mammalian cells. However, how lipids are exchanged between these two organelles is not understood. In this study, we report that the ER-resident VAMP-associated proteins A and B (VAPA and VAPB) interact with the peroxisomal membrane protein acyl-CoA binding domain containing 5 (ACBD5) and that this interaction is required to tether the two organelles together, thereby facilitating the lipid exchange between them...
February 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28108524/acbd5-and-vapb-mediate-membrane-associations-between-peroxisomes-and-the-er
#5
Joseph L Costello, Inês G Castro, Christian Hacker, Tina A Schrader, Jeremy Metz, Dagmar Zeuschner, Afsoon S Azadi, Luis F Godinho, Victor Costina, Peter Findeisen, Andreas Manner, Markus Islinger, Michael Schrader
Peroxisomes (POs) and the endoplasmic reticulum (ER) cooperate in cellular lipid metabolism and form tight structural associations, which were first observed in ultrastructural studies decades ago. PO-ER associations have been suggested to impact on a diverse number of physiological processes, including lipid metabolism, phospholipid exchange, metabolite transport, signaling, and PO biogenesis. Despite their fundamental importance to cell metabolism, the mechanisms by which regions of the ER become tethered to POs are unknown, in particular in mammalian cells...
February 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28057298/amyotrophic-lateral-sclerosis-pathogenesis-converges-on-defects-in-protein-homeostasis-associated-with-tdp-43-mislocalization-and-proteasome-mediated-degradation-overload
#6
G Lin, D Mao, H J Bellen
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects upper and/or lower motor neurons. It usually affects people between the ages of 40-70. The average life expectancy is about 3-5 years after diagnosis and there is no effective cure available. Identification of variants in more than 20 different loci has provided insight into the pathogenic molecular mechanisms mediating disease pathogenesis. In this review, we focus on seven ALS-causing genes: TDP-43, FUS, C9orf72, VCP, UBQLN2, VAPB and SOD-1, which encompass about 90% of the variants causing familial ALS...
2017: Current Topics in Developmental Biology
https://www.readbyqxmd.com/read/27998932/toxin-inhibition-in-c-crescentus-vapbc1-is-mediated-by-a-flexible-pseudo-palindromic-protein-motif-and-modulated-by-dna-binding
#7
Kirstine L Bendtsen, Kehan Xu, Majbritt Luckmann, Kristoffer S Winther, Shiraz A Shah, Christian N S Pedersen, Ditlev E Brodersen
Expression of bacterial type II toxin-antitoxin (TA) systems is regulated at the transcriptional level through direct binding of the antitoxin to pseudo-palindromic sequences on operator DNA. In this context, the toxin functions as a co-repressor by stimulating DNA binding through direct interaction with the antitoxin. Here, we determine crystal structures of the complete 90 kDa heterooctameric VapBC1 complex from Caulobacter crescentus CB15 both in isolation and bound to its cognate DNA operator sequence at 1...
December 19, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27994956/identifying-suitable-reference-genes-for-gene-expression-analysis-in-developing-skeletal-muscle-in-pigs
#8
Guanglin Niu, Yalan Yang, YuanYuan Zhang, Chaoju Hua, Zishuai Wang, Zhonglin Tang, Kui Li
The selection of suitable reference genes is crucial to accurately evaluate and normalize the relative expression level of target genes for gene function analysis. However, commonly used reference genes have variable expression levels in developing skeletal muscle. There are few reports that systematically evaluate the expression stability of reference genes across prenatal and postnatal developing skeletal muscle in mammals. Here, we used quantitative PCR to examine the expression levels of 15 candidate reference genes (ACTB, GAPDH, RNF7, RHOA, RPS18, RPL32, PPIA, H3F3, API5, B2M, AP1S1, DRAP1, TBP, WSB, and VAPB) in porcine skeletal muscle at 26 different developmental stages (15 prenatal and 11 postnatal periods)...
2016: PeerJ
https://www.readbyqxmd.com/read/27978769/genetic-analysis-of-patients-with-familial-and-sporadic-amyotrophic-lateral-sclerosis-in-a-brazilian-research-center
#9
Gerson Chadi, Jessica Ruivo Maximino, Frederico Mennucci de Haidar Jorge, FabríCIO Castro dE Borba, Joyce Meire Gilio, Dagoberto Callegaro, Camila GalvãO Lopes, Samantha Nakamura Dos Santos, Gabriela Natania Sales Rebelo
OBJECTIVE: To investigate gene mutations in familial form (FALS) and sporadic form (SALS) of amyotrophic lateral sclerosis (ALS) in a highly miscegenated population. METHODS: Frequencies of mutations in the C9orfF72, TARDBP, SOD1, FUS and VAPB genes were investigated in a cohort of FALS (n = 39) and SALS (n = 189) subjects from the Research Centre of the University of São Paulo School of Medicine. All patients were subjected to C9orf72 and TARDBP analyses...
December 15, 2016: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/27790792/als-associated-endoplasmic-reticulum-proteins-in-denervated-skeletal-muscle-implications-for-motor-neuron-disease-pathology
#10
C M Jesse, E Bushuven, P Tripathi, A Chandrasekar, C M Simon, C Drepper, A Yamoah, A Dreser, I Katona, S Johann, C Beyer, S Wagner, M Grond, S Nikolin, J Anink, D Troost, M Sendtner, A Goswami, J Weis
Alpha-motoneurons and muscle fibers are structurally and functionally interdependent. Both cell types particularly rely on endoplasmic reticulum (ER/SR) functions. Mutations of the ER proteins VAPB, SigR1 and HSP27 lead to hereditary motor neuron diseases (MNDs). Here, we determined the expression profile and localization of these ER proteins/chaperons by immunohistochemistry and immunoblotting in biopsy and autopsy muscle tissue of patients with amyotrophic lateral sclerosis (ALS) and other neurogenic muscular atrophies (NMAs) and compared these patterns to mouse models of neurogenic muscular atrophy...
October 28, 2016: Brain Pathology
https://www.readbyqxmd.com/read/27747295/influence-of-plasmid-type-on-the-replication-of-rhodococcus-equi-in-host-macrophages
#11
Jennifer M Willingham-Lane, Londa J Berghaus, Steeve Giguère, Mary K Hondalus
The soil-dwelling, saprophytic actinomycete Rhodococcus equi is a multihost, facultative intracellular pathogen of macrophages. When inhaled by susceptible foals, it causes severe bronchopneumonia. It is also a pathogen of pigs, which may develop submaxillary lymphadenitis upon exposure. R. equi isolates obtained from foals and pigs possess conjugative plasmids housing a pathogenicity island (PAI) containing a novel family of genes of unknown function called the virulence-associated protein or vap family. The PAI regions of the equine and swine plasmids differ in vap gene composition, with equine isolates possessing six vap genes, including the major virulence determinant vapA, while the PAIs of swine isolates house vapB and five other unique vap genes...
September 2016: MSphere
https://www.readbyqxmd.com/read/27672196/structural-determinants-for-antitoxin-identity-and-insulation-of-cross-talk-between-homologous-toxin-antitoxin-systems
#12
Lauren R Walling, J Scott Butler
Toxin-antitoxin (TA) systems are ubiquitous in bacteria and archaea, where they play a pivotal role in the establishment and maintenance of dormancy. Under normal growth conditions, the antitoxin neutralizes the toxin. However, under conditions of stress, such as nutrient starvation or antibiotic treatment, cellular proteases degrade the antitoxin, and the toxin functions to arrest bacterial growth. We characterized the specificity determinants of the interactions between VapB antitoxins and VapC toxins from nontypeable Haemophilus influenzae (NTHi) in an effort to gain a better understanding of how antitoxins control toxin activity and bacterial persistence...
December 15, 2016: Journal of Bacteriology
https://www.readbyqxmd.com/read/27571895/neuronal-overexpression-of-human-vapb-slows-motor-impairment-and-neuromuscular-denervation-in-a-mouse-model-of-als
#13
Ji-Yoen Kim, Ava Jang, Rohit Reddy, Wan Hee Yoon, Joanna L Jankowsky
Four mutations in the VAMP/synaptobrevin-associated protein B (VAPB) gene have been linked to amyotrophic lateral sclerosis (ALS) type 8. The mechanism by which VAPB mutations cause motor neuron disease is unclear, but studies of the most common P56S variant suggest both loss of function and dominant-negative sequestration of wild-type protein. Diminished levels of VAPB and its proteolytic cleavage fragment have also been reported in sporadic ALS cases, suggesting that VAPB loss of function may be a common mechanism of disease...
August 29, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27419871/endosome-er-contacts-control-actin-nucleation-and-retromer-function-through-vap-dependent-regulation-of-pi4p
#14
Rui Dong, Yasunori Saheki, Sharan Swarup, Louise Lucast, J Wade Harper, Pietro De Camilli
VAP (VAPA and VAPB) is an evolutionarily conserved endoplasmic reticulum (ER)-anchored protein that helps generate tethers between the ER and other membranes through which lipids are exchanged across adjacent bilayers. Here, we report that by regulating PI4P levels on endosomes, VAP affects WASH-dependent actin nucleation on these organelles and the function of the retromer, a protein coat responsible for endosome-to-Golgi traffic. VAP is recruited to retromer budding sites on endosomes via an interaction with the retromer SNX2 subunit...
July 14, 2016: Cell
https://www.readbyqxmd.com/read/27418313/als-ftd-associated-fus-activates-gsk-3%C3%AE-to-disrupt-the-vapb-ptpip51-interaction-and-er-mitochondria-associations
#15
Radu Stoica, Sébastien Paillusson, Patricia Gomez-Suaga, Jacqueline C Mitchell, Dawn Hw Lau, Emma H Gray, Rosa M Sancho, Gema Vizcay-Barrena, Kurt J De Vos, Christopher E Shaw, Diane P Hanger, Wendy Noble, Christopher Cj Miller
Defective FUS metabolism is strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), but the mechanisms linking FUS to disease are not properly understood. However, many of the functions disrupted in ALS/FTD are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. This signalling is facilitated by close physical associations between the two organelles that are mediated by binding of the integral ER protein VAPB to the outer mitochondrial membrane protein PTPIP51, which act as molecular scaffolds to tether the two organelles...
September 2016: EMBO Reports
https://www.readbyqxmd.com/read/27376329/characterization-of-the-deep-sea-streptomyces-sp-scsio-02999-derived-vapc-vapb-toxin-antitoxin-system-in-escherichia-coli
#16
Yunxue Guo, Jianyun Yao, Chenglong Sun, Zhongling Wen, Xiaoxue Wang
Toxin-antitoxin (TA) systems are small genetic elements that are ubiquitous in prokaryotes. Most studies on TA systems have focused on commensal and pathogenic bacteria; yet very few studies have focused on TAs in marine bacteria, especially those isolated from a deep sea environment. Here, we characterized a type II VapC/VapB TA system from the deep-sea derived Streptomyces sp. SCSIO 02999. The VapC (virulence-associated protein) protein belongs to the PIN (PilT N-terminal) superfamily. Overproduction of VapC strongly inhibited cell growth and resulted in a bleb-containing morphology in E...
2016: Toxins
https://www.readbyqxmd.com/read/27303903/the-vapbc1-toxin-antitoxin-complex-from-mycobacterium-tuberculosis-purification-crystallization-and-x-ray-diffraction-analysis
#17
Zuokun Lu, Han Wang, Aili Zhang, Yusheng Tan
Mycobacterium tuberculosis, a major human pathogen, encodes at least 88 toxin-antitoxin (TA) systems. Remarkably, more than half of these modules belong to the VapBC family. Under normal growth conditions, the toxicity of the toxin VapC is neutralized by the protein antitoxin VapB. When bacteria face an unfavourable environment, the antitoxin is degraded and the free toxin VapC targets important cellular processes in order to inhibit cell growth. TA systems function in many biological processes, such as in the stringent response, in biofilm formation and in drug tolerance...
June 2016: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/27234339/molecular-epidemiology-of-rhodococcus-equi-in-slaughtered-swine-cattle-and-horses-in-poland
#18
Lucjan Witkowski, Magdalena Rzewuska, Shinji Takai, Magdalena Kizerwetter-Świda, Jerzy Kita
BACKGROUND: Rhodococcus equi is an emerging zoonotic presumably foodborne pathogen. Since the data on the worldwide prevalence of R. equi in meat animals are scarce, the present study aimed to investigate the molecular epidemiology of R. equi in swine, cattle and horse carcasses intended for human consumption in Poland. RESULTS: Totally 1028 lymph node samples were examined. R. equi was isolated from 26.6 % (105/395) swine and 1.3 % (3/234) bovine healthy submaxillary lymph nodes...
May 27, 2016: BMC Microbiology
https://www.readbyqxmd.com/read/26920105/in-vitro-activity-of-ceftazidime-avibactam-against-gram-negative-pathogens-isolated-from-pneumonia-in-hospitalised-patients-including-ventilated-patients
#19
Robert K Flamm, Wright W Nichols, Helio S Sader, David J Farrell, Ronald N Jones
The activities of the novel β-lactam/non-β-lactam β-lactamase inhibitor combination ceftazidime/avibactam and comparators were evaluated against isolates from pneumonia in hospitalised patients including ventilated patients (PHP, pneumonia not designated as VABP; VABP, pneumonia in ventilated patients). Isolates were from the European-Mediterranean region (EuM), China and the USA collected in the SENTRY Antimicrobial Surveillance Program between 2009 and 2011 inclusive. A total of 2393 organisms from PHP were from the EuM, 888 from China and 3213 from the USA; from VABP patients there were 918, 97 and 692 organisms collected, respectively...
March 2016: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/26812496/oxysterol-binding-protein-orp3-rescues-the-amyotrophic-lateral-sclerosis-linked-mutant-vapb-phenotype
#20
Angie Darbyson, Johnny K Ngsee
A mutation in VAPB causes a familial form of Amyotrophic Lateral Sclerosis. The mutant protein (VAPB-P56S) is aggregate prone and blocks retrograde traffic from the endoplasmic reticulum (ER) Golgi intermediate compartment (ERGIC) including trafficking to the nuclear envelope (NE). Here we report a morphological screen where overexpression of oxysterol binding protein-related protein-3 (ORP3) rescued the mutant VAPB phenotype. It resolved the mutant VAPB-induced membrane expansions, restored solubility of the mutant protein in non-ionic detergent, and restored trafficking of Emerin to the NE...
February 1, 2016: Experimental Cell Research
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