scholarly journals Tamoxifen blocks retrograde trafficking of Shiga toxin 1 and 2 and protects against lethal toxicosis

2019 ◽  
Vol 2 (3) ◽  
pp. e201900439 ◽  
Author(s):  
Andrey S Selyunin ◽  
Steven Hutchens ◽  
Stanton F McHardy ◽  
Somshuvra Mukhopadhyay
Keyword(s):  
Shiga Toxin ◽  
Lethal Dose ◽  
Early Endosome ◽  
Base Property ◽  
Retrograde Trafficking ◽  
Golgi Transport ◽  
Late Endosomes ◽  
Genome Wide ◽  
A Genome ◽  
Using Data

Shiga toxin 1 (STx1) and 2 (STx2), produced by Shiga toxin–producingEscherichia coli, cause lethal untreatable disease. The toxins invade cells via retrograde trafficking. Direct early endosome-to-Golgi transport allows the toxins to evade degradative late endosomes. Blocking toxin trafficking, particularly at the early endosome-to-Golgi step, is appealing, but transport mechanisms of the more disease-relevant STx2 are unclear. Using data from a genome-wide siRNA screen, we discovered that disruption of the fusion of late endosomes, but not autophagosomes, with lysosomes blocked the early endosome-to-Golgi transport of STx2. A subsequent screen of clinically approved lysosome-targeting drugs identified tamoxifen (TAM) to be a potent inhibitor of the trafficking and toxicity of STx1 and STx2 in cells. The protective effect was independent of estrogen receptors but dependent on the weak base property of TAM, which allowed TAM to increase endolysosomal pH and alter endosomal dynamics. Importantly, TAM treatment enhanced survival of mice injected with a lethal dose of STx1 or STx2. Thus, it may be possible to repurpose TAM for treating Shiga toxin–producingE. coliinfections.

scholarly journals Major gene effects on exercise ventilatory threshold: the HERITAGE Family Study

2002 ◽  
Vol 93 (3) ◽  
pp. 1000-1006 ◽  
Author(s):  
Mary F. Feitosa ◽  
Steven E. Gaskill ◽  
Treva Rice ◽  
Tuomo Rankinen ◽  
Claude Bouchard ◽  
...  
Keyword(s):  
Oxygen Uptake ◽  
Ventilatory Threshold ◽  
Major Gene ◽  
Fat Free Mass ◽  
Gene Effects ◽  
Covariate Effects ◽  
Genome Wide ◽  
A Genome ◽  
Training Response ◽  
Using Data

This study investigates whether there are major gene effects on oxygen uptake at the ventilatory threshold (V˙o 2 VT) and theV˙o 2 VT maximal oxygen uptake (VT%V˙o 2 max), at baseline and in response to 20 wk of exercise training by using data on 336 whites and 160 blacks. Segregation analysis was performed on the residuals ofV˙o 2 VT and VT%V˙o 2 max. In whites, there was strong evidence of a major gene, with 3 and 2% of the sample in the upper distribution, that accounted for 52 and 43% of the variance in baseline V˙o 2 VT and VT%V˙o 2 max, respectively. There were no genotype-specific covariate effects (sex, age, weight, fat mass, and fat-free mass). The segregation results were inconclusive for the training response in whites, and for the baseline and training response in blacks, probably due to insufficient power because of reduced sample sizes or smaller gene effect or both. The strength of the genetic evidence for V˙o 2 VT and VT%V˙o 2 max suggests that these traits should be further investigated for potential relations with specific candidate genes, if they can be identified, and explored through a genome-wide scan.

Two Genetic Loci associated with Medial Collateral Ligament Injury

2017 ◽  
Vol 38 (07) ◽  
pp. 501-507 ◽  
Author(s):  
Andrew Roos ◽  
Andy Avins ◽  
Marwa Ahmed ◽  
John Kleimeyer ◽  
Thomas Roos ◽  
...  
Keyword(s):  
Medial Collateral Ligament ◽  
Ligament Injury ◽  
Genetic Loci ◽  
Collateral Ligament ◽  
Environment And Health ◽  
Medial Collateral Ligament Injury ◽  
Genome Wide ◽  
A Genome ◽  
Competitive Athletes ◽  
Using Data

AbstractMedial collateral ligament (MCL) injuries are a common knee injury, especially in competitive athletes. Identifying genetic loci associated with MCL injury could shed light on its etiology. A genome-wide association screen was performed using data from the Research Program in Genes, Environment and Health (RPGEH) including 1 572 cases of MCL injury and 100 931 controls. 2 SNPs (rs80351309 and rs6083471) showed an association with MCL injury at genome-wide significance (p<5×10−8) with moderate effects (odds ratios=2.12 and 1.57, respectively). For rs80351309, the genotypes were imputed with only moderate accuracy, so this SNP should be viewed with caution until its association with MCL injury can be validated. The SNPs rs80351309 and rs6083471 show a statistically significant association with MCL injury. It will be important to replicate this finding in future studies.

scholarly journals ARF4-mediated Retrograde Trafficking Drives Chemoresistance in Glioblastoma

2021 ◽  
Author(s):  
Shreya Budhiraja ◽  
Shivani Baisiwala ◽  
Ella Perrault ◽  
Sia Cho ◽  
Khizar Nandoliya ◽  
...  
Keyword(s):  
Retrograde Transport ◽  
Common Type ◽  
High Rate ◽  
Recurrence Rates ◽  
Retrograde Trafficking ◽  
Genome Wide ◽  
Promising Therapeutic Target ◽  
Significant Survival ◽  
A Genome ◽  
Resistance To Chemotherapy

Glioblastoma (GBM) is the most common type of adult malignant brain tumor, with a median survival of only 21 months. This is partly due to the high rate of resistance to conventional therapy, including temozolomide (TMZ), leading to recurrence rates close to 100%. It still remains unknown what drives the development of this resistance. To identify the unknown genes driving the development of this resistance, we performed a genome-wide CRISPR knockout screen comparing a DMSO-treated population with a TMZ-treated population over 14 days. We identified 4 previously unstudied genes – ARF4, PLAA, SPTLC1, and PIGK – that showed significant elevations in expression in recurrent tumors in patient datasets, along with significant survival benefits corresponding to low gene expression. Further investigation of ARF4, known to be involved in retrograde trafficking, allowed us to identify a mechanism of resistance that is mediated by increased retrograde transport of EGFR into the nucleus. Ultimately, our CRISPR-Cas9 screen has identified a promising therapeutic target, ARF4, which may drive GBM's high resistance to chemotherapy.

scholarly journals Targeting the Early Endosome-to-Golgi Transport of Shiga Toxins as a Therapeutic Strategy

Toxins ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 342
Author(s):  
Danyang Li ◽  
Andrey Selyunin ◽  
Somshuvra Mukhopadhyay
Keyword(s):  
Small Molecule ◽  
Shiga Toxin ◽  
Molecular Mechanisms ◽  
Small Molecule Inhibitors ◽  
Early Endosome ◽  
Antibiotics Resistance ◽  
Golgi Transport ◽  
Early Endosomes ◽  
Life Threatening ◽  
Ab5 Toxins

Shiga toxin (STx) produced by Shigella and closely related Shiga toxin 1 and 2 (STx1 and STx2) synthesized by Shiga toxin-producing Escherichia coli (STEC) are bacterial AB5 toxins. All three toxins target kidney cells and may cause life-threatening renal disease. While Shigella infections can be treated with antibiotics, resistance is increasing. Moreover, antibiotic therapy is contraindicated for STEC, and there are no definitive treatments for STEC-induced disease. To exert cellular toxicity, STx, STx1, and STx2 must undergo retrograde trafficking to reach their cytosolic target, ribosomes. Direct transport from early endosomes to the Golgi apparatus is an essential step that allows the toxins to bypass degradative late endosomes and lysosomes. The essentiality of this transport step also makes it an ideal target for the development of small-molecule inhibitors of toxin trafficking as potential therapeutics. Here, we review the recent advances in understanding the molecular mechanisms of the early endosome-to-Golgi transport of STx, STx1, and STx2, as well as the development of small-molecule inhibitors of toxin trafficking that act at the endosome/Golgi interface.

scholarly journals Early endosomes and endosomal coatomer are required for autophagy

2009 ◽  
Vol 185 (2) ◽  
pp. 305-321 ◽  
Author(s):  
Minoo Razi ◽  
Edmond Y.W. Chan ◽  
Sharon A. Tooze
Keyword(s):  
Early Endosome ◽  
Autophagic Flux ◽  
Loss Of Function ◽  
Ubiquitinated Proteins ◽  
Golgi Transport ◽  
Late Endosomes ◽  
Early Endosomes ◽  
Endosomal Pathway ◽  
Endosome Maturation ◽  
Autophagy Inhibition

Autophagy, an intracellular degradative pathway, maintains cell homeostasis under normal and stress conditions. Nascent double-membrane autophagosomes sequester and enclose cytosolic components and organelles, and subsequently fuse with the endosomal pathway allowing content degradation. Autophagy requires fusion of autophagosomes with late endosomes, but it is not known if fusion with early endosomes is essential. We show that fusion of AVs with functional early endosomes is required for autophagy. Inhibition of early endosome function by loss of COPI subunits (β′, β, or α) results in accumulation of autophagosomes, but not an increased autophagic flux. COPI is required for ER-Golgi transport and early endosome maturation. Although loss of COPI results in the fragmentation of the Golgi, this does not induce the formation of autophagosomes. Loss of COPI causes defects in early endosome function, as both transferrin recycling and EGF internalization and degradation are impaired, and this loss of function causes an inhibition of autophagy, an accumulation of p62/SQSTM-1, and ubiquitinated proteins in autophagosomes.

scholarly journals PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation

2021 ◽  
Author(s):  
Stephanie K. See ◽  
Merissa Chen ◽  
Sophie Bax ◽  
Ruilin Tian ◽  
Amanda Woerman ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Neurodegenerative Diseases ◽  
Human Cell ◽  
Therapeutic Target ◽  
Therapeutic Strategies ◽  
Early Endosome ◽  
Potential Therapeutic Target ◽  
Critical Step ◽  
Genome Wide ◽  
A Genome

ABSTRACTThe inter-cellular prion-like propagation of α-synuclein aggregation is emerging as an important mechanism driving the progression of neurodegenerative diseases including Parkinson’s disease and multiple system atrophy (MSA). To discover therapeutic strategies reducing the spread of α-synuclein aggregation, we performed a genome-wide CRISPR interference screen in a human cell-based model. We discovered that inhibiting PIKfyve dramatically reduced α-synuclein aggregation induced with both recombinant α-synuclein fibrils and fibrils isolated from MSA patient brain. While PIKfyve inhibition did not affect fibril uptake or α-synuclein clearance or secretion, it reduced α-synuclein trafficking from the early endosome to the lysosome, thereby limiting fibril escape from the lysosome and reducing the amount of fibrils that reach cytosolic α-synuclein to induce aggregation. These findings point to the endolysosomal transport of fibrils as a critical step in the propagation of α-synuclein aggregation and a potential therapeutic target.

scholarly journals Variants in urate transporters, ADH1B, GCKR and MEPE genes associate with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank

2021 ◽  
pp. annrheumdis-2020-219796
Author(s):  
Gabriela Sandoval-Plata ◽  
Kevin Morgan ◽  
Abhishek Abhishek
Keyword(s):  
Genome Wide Association Study ◽  
Predictive Ability ◽  
Serum Urate ◽  
Polygenic Risk Score ◽  
Nucleotide Polymorphisms ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
Using Data ◽  
The Uk

ObjectivesTo perform a genome-wide association study (GWAS) of gout cases versus asymptomatic hyperuricaemia (AH) controls, and gout cases versus normouricaemia controls, and to generate a polygenic risk score (PRS) to determine gout-case versus AH-control status.MethodsGout cases and AH controls (serum urate (SU) ≥6.0 mg/dL) from the UK Biobank were divided into discovery (4934 cases, 56 948 controls) and replication (2115 cases, 24 406 controls) cohorts. GWAS was conducted and PRS generated using summary statistics in discovery cohort as the base dataset and the replication cohort as the target dataset. The predictive ability of the model was evaluated. GWAS were performed to identify variants associated with gout compared with normouricaemic controls using SU <6.0 mg/dL and <7.0 mg/dL thresholds, respectively.ResultsThirteen independent single nucleotide polymorphisms (SNPs) in ABCG2, SLC2A9, SLC22A11, GCKR, MEPE, PPM1K-DT, LOC105377323 and ADH1B reached genome-wide significance and replicated as predictors of AH to gout transition. Twelve of 13 associations were novel for this transition, and rs1229984 (ADH1B) was identified as GWAS locus for gout for the first time. The best PRS model was generated from association data of 17 SNPs; and had predictive ability of 58.5% that increased to 69.2% on including demographic factors. Two novel SNPs rs760077(MTX1) and rs3800307(PRSS16) achieved GWAS significance for association with gout compared with normouricaemic controls using both SU thresholds.ConclusionThe association of urate transporters with gout supports the central role of hyperuricaemia in its pathogenesis. Larger GWAS are required to identify if variants in inflammatory pathways contribute to progression from AH to gout.

scholarly journals FHIP and FTS proteins are critical for dynein-mediated transport of early endosomes in Aspergillus

2014 ◽  
Vol 25 (14) ◽  
pp. 2181-2189 ◽  
Author(s):  
Xuanli Yao ◽  
Xiangfeng Wang ◽  
Xin Xiang
Keyword(s):  
Aspergillus Nidulans ◽  
Protein Level ◽  
Cytoplasmic Dynein ◽  
Early Endosome ◽  
Human Homologue ◽  
Genome Wide ◽  
A Genome ◽  
Early Endosomes ◽  
Microtubule Motor

The minus end–directed microtubule motor cytoplasmic dynein transports various cellular cargoes, including early endosomes, but how dynein binds to its cargo remains unclear. Recently fungal Hook homologues were found to link dynein to early endosomes for their transport. Here we identified FhipA in Aspergillus nidulans as a key player for HookA (A. nidulans Hook) function via a genome-wide screen for mutants defective in early-endosome distribution. The human homologue of FhipA, FHIP, is a protein in the previously discovered FTS/Hook/FHIP (FHF) complex, which contains, besides FHIP and Hook proteins, Fused Toes (FTS). Although this complex was not previously shown to be involved in dynein-mediated transport, we show here that loss of either FhipA or FtsA (A. nidulans FTS homologue) disrupts HookA–early endosome association and inhibits early endosome movement. Both FhipA and FtsA associate with early endosomes, and interestingly, while FtsA–early endosome association requires FhipA and HookA, FhipA–early endosome association is independent of HookA and FtsA. Thus FhipA is more directly linked to early endosomes than HookA and FtsA. However, in the absence of HookA or FtsA, FhipA protein level is significantly reduced. Our results indicate that all three proteins in the FtsA/HookA/FhipA complex are important for dynein-mediated early endosome movement.

Establishment of a genome-wide RNAi screen; Identification of novel genes involved in clonal maintenance of ALL

2014 ◽  
Vol 226 (03) ◽  
Author(s):  
F Ponthan ◽  
D Pal ◽  
J Vormoor ◽  
O Heidenreich
Keyword(s):  
Rnai Screen ◽  
Novel Genes ◽  
Genome Wide ◽  
A Genome
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