scholarly journals Fungal extracellular vesicles are involved in intraspecies intracellular communication

2021 ◽  
Author(s):  
Tamires Aparecida Bittencourt ◽  
Otavio Hatanaka ◽  
Andre Moreira Pessoni ◽  
Mateus Silveira Freitas ◽  
Gabriel Trentin ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Fungal Infections ◽  
Uv Light ◽  
Paracoccidioides Brasiliensis ◽  
Biological Information ◽  
Fungal Host ◽  
Host Interaction

Fungal infections are associated with high mortality rates in humans. The risk of fungal diseases creates the urgent need to broaden the knowledge base regarding their pathophysiology. In this sense, the role of extracellular vesicles (EVs) has been described to convey biological information and participate in the fungal-host interaction process. EVs play many roles, including cellular physiology, responding to environmental cues, mediating a complex circuit of cellular communication in bidirectional crosstalk with other organisms, and the communication between fungal cells has been speculated. This study demonstrated the intra species uptake of EVs in fungi, including Candida albicans, Aspergillus fumigatus, and Paracoccidioides brasiliensis, and the effects triggered by EVs in fungal cells. In C. albicans, we evaluated the involvement of EVs in yeast to hyphae transition, whilst in P. brasiliensis and A. fumigatus the function of EVs as stress transducers was investigated. Both P. brasiliensis and A. fumigatus were exposed to an inhibitor of glycosylation or UV light, respectively. The results demonstrated the role of EVs in regulating the expression of target genes and phenotype features. The EVs treatment induced cellular proliferation and boosted the transition yeast to hyphal transition in C. albicans, while they enhanced stress signals in A. fumigatus and P. brasiliensis, establishing a role for EVs in fungal intra species communication. Thus, fungal EVs regulate the virulence and adaptive traits in fungal interaction systems as potent message effectors, and understanding their effects and mechanism(s) of action could be exploited in antifungal therapies.

scholarly journals Fungal Extracellular Vesicles Are Involved in Intraspecies Intracellular Communication

mBio ◽  
2022 ◽  
Author(s):  
Tamires A. Bitencourt ◽  
Otavio Hatanaka ◽  
Andre M. Pessoni ◽  
Mateus S. Freitas ◽  
Gabriel Trentin ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Aspergillus Fumigatus ◽  
Extracellular Vesicles ◽  
Target Genes ◽  
Paracoccidioides Brasiliensis ◽  
Content Type ◽  
Intracellular Communication

Here, we report a study about extracellular vesicles (EVs) as communication mediators in fungi. Our results demonstrated the role of EVs from Candida albicans , Aspergillus fumigatus , and Paracoccidioides brasiliensis regulating the expression of target genes and phenotype features.

scholarly journals Post-Translational Modifications Drive Success and Failure of Fungal–Host Interactions

2021 ◽  
Vol 7 (2) ◽  
pp. 124
Author(s):  
Charmaine Retanal ◽  
Brianna Ball ◽  
Jennifer Geddes-McAlister
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Treatment Options ◽  
Global Scale ◽  
Host Cells ◽  
Candida Spp ◽  
Post Translational Modifications ◽  
Fungal Host ◽  
Resistant Species

Post-translational modifications (PTMs) change the structure and function of proteins and regulate a diverse array of biological processes. Fungal pathogens rely on PTMs to modulate protein production and activity during infection, manipulate the host response, and ultimately, promote fungal survival. Given the high mortality rates of fungal infections on a global scale, along with the emergence of antifungal-resistant species, identifying new treatment options is critical. In this review, we focus on the role of PTMs (e.g., phosphorylation, acetylation, ubiquitination, glycosylation, and methylation) among the highly prevalent and medically relevant fungal pathogens, Candida spp., Aspergillus spp., and Cryptococcus spp. We explore the role of PTMs in fungal stress response and host adaptation, the use of PTMs to manipulate host cells and the immune system upon fungal invasion, and the importance of PTMs in conferring antifungal resistance. We also provide a critical view on the current knowledgebase, pose questions key to our understanding of the intricate roles of PTMs within fungal pathogens, and provide research opportunities to uncover new therapeutic strategies.

Accumulation of soluble and nucleolar-associated p53 proteins following cellular stress

2001 ◽  
Vol 114 (10) ◽  
pp. 1867-1873 ◽  
Author(s):  
S.A. Klibanov ◽  
H.M. O'Hagan ◽  
M. Ljungman
Keyword(s):  
Target Genes ◽  
Uv Light ◽  
Human Fibroblasts ◽  
Proteasome Inhibition ◽  
Tumor Suppressor P53 ◽  
Mdm2 Protein ◽  
Transcription Inhibitor ◽  
Cellular Stresses ◽  
In Cells

The tumor suppressor p53 is a nucleocytoplasmic shuttling protein that accumulates in the nucleus of cells exposed to various cellular stresses. One important role of nuclear p53 is to mobilize a stress response by transactivating target genes such as the p21(Waf1) gene. In this study, we investigated more closely the localization of p53 in cells following various stresses. Immunocytochemistry of fixed human fibroblasts treated with either UV light, the kinase and transcription inhibitor DRB or the proteasome inhibitor MG132 revealed abundant p53 localized to the nucleus. When cells treated with UV or DRB were permeabilized prior to fixation to allow soluble proteins to diffuse, the nuclear p53 signal was abolished. However, in cells treated with MG132, residual p53 localized to distinct large foci. Furthermore, nucleolin co-localized with p53 to these foci, suggesting that these foci were nucleolar structures. Interestingly, the MDM2 protein was found to co-localize with p53 to nucleolar structures following proteasome inhibition. Our results suggest that the p53 proteins accumulating in the nucleus following UV-irradiation or blockage of transcription are freely soluble and, thus, should be able to roam the nucleus to ensure high occupancy of p53 binding sites. However, inhibition of proteasome activity may be a unique stress in that it leads to the sequestering of p53 proteins to the nucleolus, thereby blunting the p53-mediated transactivation of target genes.

scholarly journals Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

2020 ◽  
Vol 21 (4) ◽  
pp. 1377
Author(s):  
Pavan Kumar Dhanyamraju ◽  
Soumya Iyer ◽  
Gayle Smink ◽  
Yevgeniya Bamme ◽  
Preeti Bhadauria ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
Chromatin Remodeling ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Lymphoblastic Leukemia ◽  
Regulatory Elements ◽  
Binding Motif ◽  
Functional Inactivation

Regulation of oncogenic gene expression by transcription factors that function as tumor suppressors is one of the major mechanisms that regulate leukemogenesis. Understanding this complex process is essential for explaining the pathogenesis of leukemia as well as developing targeted therapies. Here, we provide an overview of the role of Ikaros tumor suppressor and its role in regulation of gene transcription in acute leukemia. Ikaros (IKZF1) is a DNA-binding protein that functions as a master regulator of hematopoiesis and the immune system, as well as a tumor suppressor in acute lymphoblastic leukemia (ALL). Genetic alteration or functional inactivation of Ikaros results in the development of high-risk leukemia. Ikaros binds to the specific consensus binding motif at upstream regulatory elements of its target genes, recruits chromatin-remodeling complexes and activates or represses transcription via chromatin remodeling. Over the last twenty years, a large number of Ikaros target genes have been identified, and the role of Ikaros in the regulation of their expression provided insight into the mechanisms of Ikaros tumor suppressor function in leukemia. Here we summarize the role of Ikaros in the regulation of the expression of the genes whose function is critical for cellular proliferation, development, and progression of acute lymphoblastic leukemia.

scholarly journals Circulating MicroRNAs in Extracellular Vesicles as Potential Biomarkers of Alcohol-Induced Neuroinflammation in Adolescence: Gender Differences

2020 ◽  
Vol 21 (18) ◽  
pp. 6730
Author(s):  
Francesc Ibáñez ◽  
Juan R. Ureña-Peralta ◽  
Pilar Costa-Alba ◽  
Jorge-Luis Torres ◽  
Francisco-Javier Laso ◽  
...  
Keyword(s):  
Gender Differences ◽  
Extracellular Vesicles ◽  
Target Genes ◽  
Alcohol Intoxication ◽  
Peripheral Circulation ◽  
Female Adolescents ◽  
Circulating Micrornas ◽  
Male Adolescents ◽  
First Time

Current studies evidence the role of miRNAs in extracellular vesicles (EVs) as key regulators of pathological processes, including neuroinflammation and neurodegeneration. As EVs can cross the blood–brain barrier, and EV miRNAs are very stable in peripheral circulation, we evaluated the potential gender differences in inflammatory-regulated miRNAs levels in human and murine plasma EVs derived from alcohol-intoxicated female and male adolescents, and whether these miRNAs could be used as biomarkers of neuroinflammation. We demonstrated that while alcohol intoxication lowers anti-inflammatory miRNA (mir-146a-5p, mir-21-5p, mir-182-5p) levels in plasma EVs from human and mice female adolescents, these EV miRNAs increased in males. In mice brain cortices, ethanol treatment lowers mir-146a-5p and mir-21-5p levels, while triggering a higher expression of inflammatory target genes (Traf6, Stat3, and Camk2a) in adolescent female mice. These results indicate, for the first time, that female and male adolescents differ as regards the ethanol effects associated with the inflammatory-related plasma miRNAs EVs profile, and suggest that female adolescents are more vulnerable than males to the inflammatory effects of binge alcohol drinking. These findings also support the view that circulating miRNAs in EVs could be useful biomarkers for screening ethanol-induced neuroinflammation and brain damage in adolescence.

scholarly journals Two functionally redundant FK506-binding proteins regulate multidrug resistance gene expression and govern azole antifungal resistance

2021 ◽  
Author(s):  
Romila Moirangthem ◽  
Kundan Kumar ◽  
Rupinder Kaur
Keyword(s):  
Gene Expression ◽  
Binding Proteins ◽  
Target Genes ◽  
Fungal Infections ◽  
Antifungal Resistance ◽  
Azole Resistance ◽  
Multidrug Resistance Gene ◽  
Protein Levels ◽  
Fk506 Binding Proteins

Increasing resistance to antifungal therapy is an impediment to effective treatment of fungal infections. Candida glabrata is an opportunistic human fungal pathogen which is inherently less susceptible to cost-effective azole antifungals. Gain-of-function mutations in the Zn-finger pleiotropic drug resistance transcriptional activator-encoding gene, CgPDR1, are the most prevalent cause of azole resistance in clinical settings. CgPDR1 is also transcriptionally activated upon azole exposure, however, factors governing CgPDR1 gene expression are not yet fully understood. Here, we have uncovered a novel role for two FK506-binding proteins, CgFpr3 and CgFpr4, in regulation of the CgPDR1 regulon. We show that CgFpr3 and CgFpr4 possess peptidyl-prolyl isomerase domain, and act redundantly to control CgPDR1 expression, as Cgfpr3Δ4Δ mutant displayed elevated expression of CgPDR1 gene, along with overexpression of its target genes, CgCDR1, CgCDR2 and CgSNQ2, that code for ATP-binding cassette multidrug transporters. Further, CgFpr3 and CgFpr4 are required for maintenance of histone H3 and H4 protein levels, and fluconazole exposure leads to elevated H3 and H4 protein levels. Consistent with a role of histone proteins in azole resistance, disruption of genes coding for the histone demethylase CgRph1 and histone H3K36-specific methyltransferase CgSet2 leads to increased and decreased susceptibility to fluconazole, respectively, with Cgrph1Δ mutant displaying significantly lower basal expression of CgPDR1 and CgCDR1 genes. These data underscore a hitherto unknown role of histone methylation in modulating the most common azole antifungal resistance mechanism. Altogether, our findings establish a link between CgFpr-mediated histone homeostasis and CgPDR1 gene expression, and implicate CgFpr in virulence of C. glabrata.

Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates

2021 ◽  
Vol 13 (584) ◽  
pp. eabb0202
Author(s):  
Qingju Li ◽  
Yinchuan Xu ◽  
Kaiqi Lv ◽  
Yingchao Wang ◽  
Zhiwei Zhong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Extracellular Vesicles ◽  
Nonhuman Primates ◽  
Target Genes ◽  
Cardiac Fibroblasts ◽  
Vascular Density ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Stem cell–derived small extracellular vesicles (sEVs) promote angiogenesis after myocardial infarction (MI). However, the components of sEVs that contribute to these effects and the safety and efficiency of engineered sEV treatment for MI remain unresolved. Here, we observed improved cardiac function, enhanced vascular density, and smaller infarct size in mice treated with the sEVs from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) (HP-sEVs) than in mice treated with normoxia-preconditioned (N) MSCs (N-sEVs). MicroRNA profiling revealed a higher abundance of miR-486-5p in HP-sEVs than in N-sEVs, and miR-486-5p inactivation abolished the benefit of HP-sEV treatment, whereas miR-486-5p up-regulation enhanced the benefit of N-sEV treatment. Matrix metalloproteinase 19 (MMP19) abundance was lower in HP-sEV–treated than N-sEV–treated mouse hearts but was enriched in cardiac fibroblasts (CFs), and Mmp19 was identified as one of the target genes of miR-486-5p. Conditioned medium from CFs that overexpressed miR-486-5p or silenced MMP19 increased the angiogenic activity of endothelial cells; however, medium from CFs that simultaneously overexpressed Mmp19 and miR-486-5p abolished this effect. Mmp19 silencing in CFs reduced the cleavage of extracellular vascular endothelial growth factor (VEGF). Furthermore, miR-486-5p–overexpressing N-sEV treatment promoted angiogenesis and cardiac recovery without increasing arrhythmia complications in a nonhuman primate (NHP) MI model. Collectively, this study highlights the key role of sEV miR-486-5p in promoting cardiac angiogenesis via fibroblastic MMP19-VEGFA cleavage signaling. Delivery of miR-486-5p–engineered sEVs safely enhanced angiogenesis and cardiac function in an NHP MI model and may promote cardiac repair.

scholarly journals TNF-α Modulates P-Glycoprotein Expression and Contributes to Cellular Proliferation via Extracellular Vesicles

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 500 ◽  
Author(s):  
Tandressa S. Berguetti ◽  
Lucas S. P. Quintaes ◽  
Thais Hancio Pereira ◽  
Marcela Robaina ◽  
André Cruz ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Cellular Proliferation ◽  
Proliferation Index ◽  
Necrosis Factor Alpha ◽  
P Glycoprotein ◽  
Tnf Α ◽  
Factor Alpha ◽  
Membrane Microparticles

P-glycoprotein (Pgp/ABCB1) overexpression is associated with multidrug resistance (MDR) phenotype and, consequently, failure in cancer chemotherapy. However, molecules involved in cell death deregulation may also support MDR. Tumor necrosis factor-alpha (TNF-α) is an important cytokine that may trigger either death or tumor growth. Here, we examined the role of cancer cells in self-maintenance and promotion of cellular malignancy through the transport of Pgp and TNF-α molecules by extracellular vesicles (membrane microparticles (MP)). By using a classical MDR model in vitro, we identified a positive correlation between endogenous TNF-α and Pgp, which possibly favored a non-cytotoxic effect of recombinant TNF-α (rTNF-α). We also found a positive feedback involving rTNF-α incubation and TNF-α regulation. On the other hand, rTNF-α induced a reduction in Pgp expression levels and contributed to a reduced Pgp efflux function. Our results also showed that parental and MDR cells spontaneously released MP containing endogenous TNF-α and Pgp. However, these MP were unable to transfer their content to non-cancer recipient cells. Nevertheless, MP released from parental and MDR cells elevated the proliferation index of non-tumor cells. Collectively, our results suggest that Pgp and endogenous TNF-α positively regulate cancer cell malignancy and contribute to changes in normal cell behavior through MP.

scholarly journals Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Debora Giunti ◽  
Chiara Marini ◽  
Benedetta Parodi ◽  
Cesare Usai ◽  
Marco Milanese ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mode Of Action ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Mapk Signaling ◽  
Target Cells ◽  
Inflammatory Phenotype ◽  
Lateral Sclerosis

AbstractMesenchymal stromal/stem cells (MSCs) are characterized by neuroprotective, immunomodulatory, and neuroregenerative properties, which support their therapeutic potential for inflammatory/neurodegenerative diseases, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). One mode of action through which MSCs exert their immunomodulatory effects is release of extracellular vesicles that carry proteins, mRNAs, and microRNAs (miRNAs), which, once transferred, modify the function of target cells. We identified nine miRNAs significantly dysregulated in IFN-γ-primed MSCs, but present at different levels in their derived small extracellular vesicles (s-EV). We show that miR-467f and miR-466q modulate the pro-inflammatory phenotype of activated N9 microglia cells and of primary microglia acutely isolated from late symptomatic SOD1G93A mice, a murine ALS model, by downregulating Tnf and Il1b expression. Further analysis of the mode of action of miR-467f and miR-466q indicated that they dampen the pro-inflammatory phenotype of microglia by modulating p38 MAPK signaling pathway via inhibition of expression of their target genes, Map3k8 and Mk2. Finally, we demonstrated that in vivo administration of s-EV leads to decreased expression of neuroinflammation markers in the spinal cord of EAE-affected mice, albeit without affecting disease course. Overall, our data suggest that MSC-derived exosomes could affect neuroinflammation possibly through specific immunomodulatory miRNAs acting on microglia.

scholarly journals Responses of Pathogenic and Nonpathogenic Yeast Species to Steroids Reveal the Functioning and Evolution of Multidrug Resistance Transcriptional Networks

2007 ◽  
Vol 7 (1) ◽  
pp. 68-77 ◽  
Author(s):  
Dibyendu Banerjee ◽  
Gaelle Lelandais ◽  
Sudhanshu Shukla ◽  
Gauranga Mukhopadhyay ◽  
Claude Jacq ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Target Genes ◽  
Fungal Infections ◽  
Expression Profiles ◽  
Membrane Properties ◽  
Transcriptional Networks ◽  
Pleiotropic Drug Resistance ◽  
Structures And Properties ◽  
Conserved Core

ABSTRACT Steroids are known to induce pleiotropic drug resistance states in hemiascomycetes, with tremendous potential consequences for human fungal infections. Our analysis of gene expression in Saccharomyces cerevisiae and Candida albicans cells subjected to three different concentrations of progesterone revealed that their pleiotropic drug resistance (PDR) networks were strikingly sensitive to steroids. In S. cerevisiae, 20 of the Pdr1p/Pdr3p target genes, including PDR3 itself, were rapidly induced by progesterone, which mimics the effects of PDR1 gain-of-function alleles. This unique property allowed us to decipher the respective roles of Pdr1p and Pdr3p in PDR induction and to define functional modules among their target genes. Although the expression profiles of the major PDR transporters encoding genes ScPDR5 and CaCDR1 were similar, the S. cerevisiae global PDR response to progesterone was only partly conserved in C. albicans. In particular, the role of Tac1p, the main C. albicans PDR regulator, in the progesterone response was apparently restricted to five genes. These results suggest that the C. albicans and S. cerevisiae PDR networks, although sharing a conserved core regarding the regulation of membrane properties, have different structures and properties. Additionally, our data indicate that other as yet undiscovered regulators may second Tac1p in the C. albicans drug response.

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