Multivesicular body formation enhancement and exosome release during endoplasmic reticulum stress

Kanemoto, Soshi; Nitani, Ryota; Murakami, Tatsuhiko; Kaneko, Masayuki; Asada, Rie; Matsuhisa, Koji; Saito, Atsushi; Imaizumi, Kazunori

doi:10.1016/j.bbrc.2016.10.019

Cited by 130 publications

(91 citation statements)

References 43 publications

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“…sensing. An explanation is that in atorvastatin treated S288C, ER-stress is mainly buffered by multivesicular body (autophagy) associated genes as seen in the SAFE analysis ( Figure 2C) similar to observations reported for C. elegans 59 and human cells 60 whereas in the resistant strains atorvastatin toxicity is buffered by a more robust folding/ERAD system ( Figure 6).…”

Section: Discussionsupporting

confidence: 76%

Master regulators of genetic interaction networks mediating statin drug response inSaccharomyces cerevisiaevary with genetic background

Busby

Niktab

Roberts

et al. 2018

Preprint

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Determination of genetic interaction networks (GINs) surrounding drug targets identifies buffering genes and provides molecular insight into drug response in individuals. Here we used backcross methodology to create Saccharomyces cerevisiae deletion libraries in three genetic backgrounds resistant to statins, which are additional to the statin-sensitive S288C deletion library that has provided much of what is known about GINs in eukaryotes. Whole genome sequencing and linkage group analysis confirmed the genomic authenticity of the new deletion libraries. Statin response was probed by drug-gene interactions with atorvastatin and cerivastatin treatments, as well as gene-gene interactions with the statin target HMG1 and HMG2 genes or the sterol homeostatic ARV1 gene. The 20 GINs generated from these interactions were not conserved by function or topology across the four genetic backgrounds. Centrality measures and hierarchical agglomerative clustering identified master regulators that if removed collapsed the networks. Community structure distinguished a characteristic early secretory pathway pattern of gene usage in each genetic background. ER stress in statin-resistant backgrounds was buffered by protein folding genes, which was confirmed by reduced activation of the unfolded protein response in statinresistant backgrounds relative to the statin-sensitive S288C background. These network analyses of new gene deletion libraries provide insight into the complexity of GINs underlying individual drug response.Statins target HMG-CoA-reductase and are amongst the most prescribed of all therapeutic drugs 19 . However, they have significant side-effects in some individuals such as muscular myopathies 20,21 and exhibit individual variation in clinical efficacy 22 . Atorvastatin and cerivastatin are two cholesterol-lowering drugs that have the same target, HMG-CoA reductase (encoded by HMGCR in humans and the orthologous paralogues HMG1 and HMG2 in yeast), but cerivastatin is no longer FDA-approved owing to adverse side effects, suggesting that analysis of GINs in response to these drugs in different individual genetic backgrounds could be critical to fully understanding the mechanisms of these drugs. The statin drug target and sterol pathways are conserved from yeast to humans 23 , the HMG1/2 deletion has been used as a genetic mimic of statin treatment 24,25 , chemical genomic 4 analyses in yeast elucidated the cellular response to statins 26 , and genome-wide analyses in yeast identified GIs with the HMG1/2 statin drug target 13 .Deletion libraries in the yeast S288C background used in synthetic genetic array (SGA) and chemical genetic analyses have provided much of what is known about GINs in eukaryotes 10,13,27,28 . In this paper we extended the scope of the S288C literature by creating three new deletion libraries in three additional yeast strains of different genetic backgrounds. We identified GIs with atorvastatin, cerivastatin, and statin target HMG1, its functional paralog HMG2, and the sterol homeostatic ARV1 gen...

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Section: Discussionsupporting

confidence: 76%

Master regulators of genetic interaction networks mediating statin drug response inSaccharomyces cerevisiaevary with genetic background

Busby

Niktab

Roberts

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…), and their release is stimulated by ER stress (Kanemoto et al. ) such as that which occurs in cells with a disrupted TSC (Siroky et al. ).…”

Section: Resultsmentioning

confidence: 99%

“…This exploration was based on several reasons. First, such extracellular vesicles are a prominent component of renal pathophysiology (Pomatto et al 2017), and their release is stimulated by ER stress (Kanemoto et al 2016) such as that which occurs in cells with a disrupted TSC (Siroky et al 2012). Second, extracellular vesicle release as well as fusion are known to be increased in an acidic extracellular environment (Parolini et al 2009;Maas et al 2017), and the cyst fluid in the Aqp2CreTsc2 Figure 7.…”

Section: Possible Role Of Extracellular Vesicles In Disease Phenotypementioning

confidence: 99%

Tuberous sclerosis complex exhibits a new renal cystogenic mechanism

et al. 2019

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Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. While the most common renal tumor in TSC, the angiomyolipoma, exhibits a loss of heterozygosity associated with disease, we have discovered that the renal cystic epithelium is composed of type A intercalated cells that have an intact Tsc gene that have been induced to exhibit Tsc‐mutant disease phenotype. This mechanism appears to be different than that for ADPKD. The murine models described here closely resemble the human disease and both appear to be mTORC1 inhibitor responsive. The induction signaling driving cystogenesis may be mediated by extracellular vesicle trafficking.

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“…CYP4F2 is an enzyme usually found in endoplasmic reticulum. However, under stress conditions, it may be secreted with extracellular vesicles into the blood stream 34 .…”

Section: Discussionmentioning

confidence: 99%

Factors associated with platelet reactivity during dual antiplatelet therapy in patients with diabetes after acute coronary syndrome

Tatarūnas

Kupstytė-Krištaponė

Žvikas

et al. 2020

Sci Rep

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Antiplatelet drugs are prescribed without considering the diabetic status of the patient. the objective of the current investigation was to determine the impact of clinical factors, CYP4F2 enzyme and 20-hydroxyeicosatetraenoic acid (20-HETE) concentrations on high on-treatment platelet reactivity in patients with diabetes treated with antiplatelet drugs following acute coronary syndromes. A total of 667 patients were included in the study. Dual antiplatelet drug loading dosages with aspirin (300 mg) and ticagrelor (180 mg) or clopidogrel (600 mg) were prescribed to all the studied patients. testing of platelet aggregation was performed the day after loading antiplatelet drug dosages. platelet aggregation test was done according to the classical Born method. Multivariate binary regression analysis demonstrated that insulin use and higher 20-HETE concentration increased the odds of high on-treatment platelet reactivity during the initiation of antiplatelet drug therapy (OR: 3.968, 95% CI: 1.478-10.656, p = 0.006 and OR: 1.139, 95% CI: 1.073-1.210, respectively, p < 0.001). Ticagrelor use decreased the odds of developing high on-treatment platelet reactivity (OR: 0.238, 95% CI: 0.097-0.585, p = 0.002). Data from this study revealed that high on-treatment platelet reactivity during dual antiplatelet therapy in patients with diabetes may depend on such factors as insulin prescription and 20-HETE concentration.

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Multivesicular body formation enhancement and exosome release during endoplasmic reticulum stress

Cited by 130 publications

References 43 publications

Master regulators of genetic interaction networks mediating statin drug response inSaccharomyces cerevisiaevary with genetic background

Master regulators of genetic interaction networks mediating statin drug response inSaccharomyces cerevisiaevary with genetic background

Tuberous sclerosis complex exhibits a new renal cystogenic mechanism

Factors associated with platelet reactivity during dual antiplatelet therapy in patients with diabetes after acute coronary syndrome

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