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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
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...
September 26, 2016: Journal of Bacteriology
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
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
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
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
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
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...
2016: BMC Microbiology
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
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
Garvita Gupta, Jianxing Song
Hepatitis C virus (HCV) is a pathogen of global importance and nearly 200 million people are chronically infected with HCV. HCV is an enveloped single-stranded RNA virus, which is characteristic of the formation of the host membrane associated replication complex. Previous functional studies have already established that the human ER-anchored VAPB protein acts as a host factor to form a complex with HCV NS5A and NS5B, which may be established as a drug target. However, there is lacking of biophysical characterization of the structures and interfaces of the complex, partly due to the dynamic nature of the complex formation and dissociation, which is extensively involved in intrinsically-disordered domains...
2016: PloS One
Huagang Zhang, Lu Tang, Nan Zhang, Dongsheng Fan
OBJECTIVE: To explore the mutations of VAPB (vesicle associated membrane protein/synaptobrevin associated membrane protein B) in Chinese patients with familial amyotrophic lateral sclerosis (FALS). METHODS: The clinical data were collected from 40 FALS families from 2008 to 2011 and the mutations of VAPB gene screened in probands using polymerase chain reaction (PCR) and direct sequencing. RESULTS: All 40 ALS families were of autosomal dominant inheritance...
June 2, 2015: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Li Di, Hai Chen, Yuwei Da, Suobing Wang, Xin-Ming Shen
Amyotrophic lateral sclerosis (ALS) is the most prevalent fatal motor neuron disease and ~10% of cases are hereditary. Mutations associated with ALS have been identified in more than 20 genes, but ALS type 8 (ALS8), which is caused by mutations in vesicle-associated membrane protein-associated protein B (VAPB), is rare. To date, the dominant missense mutation P56S, which is in the major sperm protein domain of VAPB, has been described in nine families of Portuguese-Brazilian origin and one family of German origin...
February 2016: Journal of Neurology
Frédérique Larroquette, Lesley Seto, Perrine L Gaub, Brishna Kamal, Deeann Wallis, Roxanne Larivière, Joanne Vallée, Richard Robitaille, Hiroshi Tsuda
Missense mutations (P56S) in Vapb are associated with autosomal dominant motor neuron diseases: amyotrophic lateral sclerosis and lower motor neuron disease. Although transgenic mice overexpressing the mutant vesicle-associated membrane protein-associated protein B (VAPB) protein with neuron-specific promoters have provided some insight into the toxic properties of the mutant proteins, their role in pathogenesis remains unclear. To identify pathological defects in animals expressing the P56S mutant VAPB protein at physiological levels in the appropriate tissues, we have generated Vapb knock-in mice replacing wild-type Vapb gene with P56S mutant Vapb gene and analyzed the resulting pathological phenotypes...
November 15, 2015: Human Molecular Genetics
Celia Kun-Rodrigues, Christos Ganos, Rita Guerreiro, Susanne A Schneider, Claudia Schulte, Suzanne Lesage, Lee Darwent, Peter Holmans, Andrew Singleton, Kailash Bhatia, Jose Bras
Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent-child trios where the proband presents with typical PD to unequivocally identify de novo mutations...
December 1, 2015: Human Molecular Genetics
Francesca Navone, Paola Genevini, Nica Borgese
Autophagy plays a major role in the elimination of cellular waste components, the renewal of intracellular proteins and the prevention of the build-up of redundant or defective material. It is fundamental for the maintenance of homeostasis and especially important in post-mitotic neuronal cells, which, without competent autophagy, accumulate protein aggregates and degenerate. Many neurodegenerative diseases are associated with defective autophagy; however, whether altered protein turnover or accumulation of misfolded, aggregate-prone proteins is the primary insult in neurodegeneration has long been a matter of debate...
2015: Cells
Yukako Tokutake, Keita Yamada, Masaki Ohata, Yoshihito Obayashi, Megumi Tsuchiya, Shinichi Yonekura
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that affects upper and lower motor neurons. Since motor neurons target skeletal muscles, the maintenance system of muscles is disturbed in ALS; however, the mechanism by which this occurs is unknown. In the present study, we investigated the effects of ALS-associated P56S-vesicle-associated membrane protein-associated protein B (VAPB) (P56S-VAPB) on the IRE1-XBP1 pathway, which is involved in the unfolded protein response (UPR) of the mouse myoblast cell line (C2C12 cells)...
2015: International Journal of Molecular Sciences
Edward L Huttlin, Lily Ting, Raphael J Bruckner, Fana Gebreab, Melanie P Gygi, John Szpyt, Stanley Tam, Gabriela Zarraga, Greg Colby, Kurt Baltier, Rui Dong, Virginia Guarani, Laura Pontano Vaites, Alban Ordureau, Ramin Rad, Brian K Erickson, Martin Wühr, Joel Chick, Bo Zhai, Deepak Kolippakkam, Julian Mintseris, Robert A Obar, Tim Harris, Spyros Artavanis-Tsakonas, Mathew E Sowa, Pietro De Camilli, Joao A Paulo, J Wade Harper, Steven P Gygi
Protein interactions form a network whose structure drives cellular function and whose organization informs biological inquiry. Using high-throughput affinity-purification mass spectrometry, we identify interacting partners for 2,594 human proteins in HEK293T cells. The resulting network (BioPlex) contains 23,744 interactions among 7,668 proteins with 86% previously undocumented. BioPlex accurately depicts known complexes, attaining 80%-100% coverage for most CORUM complexes. The network readily subdivides into communities that correspond to complexes or clusters of functionally related proteins...
July 16, 2015: Cell
G H B Lara, S Takai, Y Sasaki, T Kakuda, F J P Listoni, R M Risseti, A B C de Morais, M G Ribeiro
UNLABELLED: The virulence-plasmid profile of Rhodococcus equi strains isolated from Suidae and humans is similar. Recent evidence suggests that the consumption of pork products contaminated with faeces might be a potential source of R. equi infections in humans, mainly to patients with rhodococcosis without history of contact with pigs or pig farms. This study investigated the virulence-associated genes (vapA and vapB) and plasmid profiles of R. equi among the 150 samples of small intestinal content obtained from slaughtered pigs...
September 2015: Letters in Applied Microbiology
Pavle Vrebalov Cindro, Veselin Vrebalov Cindro
Following the completion of the Human Genome Project, a lot of progress has been made in understanding the genetic basis of motor neuron diseases (MNDs) and neuropathies. Spinal Muscular Atrophies (SMA) are caused by mutations in the SMN1 gene localized on Chromosome 5q11. Amyotrophic Lateral Sclerosis (ALS) has been found to have at least 18 different types, many of them associated to different genetic loci (e.g. SOD1, ALS2, SETX, FUS, VAPB, ANG, TARDBP and others), but many of the forms have still not been associated with a particular gene...
March 2015: Collegium Antropologicum
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