Multiple roles and diverse regulation of the Ras/cAMP/protein kinase A pathway in <i>Candida albicans</i>

Huang, Guanghua; Huang, Qian; Wei, Yujia; Wang, Yan Ming; Du, Han

doi:10.1111/mmi.14148

Cited by 76 publications

(88 citation statements)

References 98 publications

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“…Huk et al suggested that deletion of RAP1B reduces the size and incidence of TC mediated by protein kinase A (PKA) in an in vivo model . Other advanced investigations implied that RAP1B is a downstream target of the PKA signal pathway, which is associated with tumorigenesis of TC . Another study reported that RAP1B plays an oncogenic role in esophageal squamous cell carcinoma by activating the Wnt/beta‐catenin cascade .…”

Section: Discussionmentioning

confidence: 99%

“…24 Other advanced investigations implied that RAP1B is a downstream target of the PKA signal pathway, which is associated with tumorigenesis of TC. 25 Another study reported that RAP1B plays an oncogenic role in esophageal squamous cell carcinoma by activating the Wnt/beta-catenin cascade. 26 RAP1B is a promising therapeutic target for the TC treatment.…”

Section: Discussionmentioning

confidence: 99%

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miR‐206 inhibits thyroid cancer proliferation and invasion by targeting RAP1B

Wang

et al. 2019

J of Cellular Biochemistry

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Thyroid cancer (TC) is one of the primary tumors arisen from endocrine system. The purpose of this study was to investigate the underlying mechanism by which RAP1B (Ras‐related protein Rap‐1b) modulates microRNA (miR)‐206 related effects on TC cells. Expression of miR‐206 and RAP1B was analyzed in cells and tissues. miR‐206 mimics or inhibitors and RAP1B vector were used in functional experiments to investigate the effects of miR‐206 and RAP1B on cell activities including proliferation, migration, and invasion. Luciferase assay was performed to explore the association between miR‐206 and RAP1B. The influence of miR‐206 on tumorigenesis of TC cells was investigated using an ex vivo model. Our results demonstrated the reduce of miR‐206 in TC tissues and cell lines in which RAP1B was increased. Overexpression of miR‐206 significantly inhibited the functional capacities of TPC‐1 cells including proliferation, invasion, and migration, most likely, through reducing the expression of RAP1B. Xenograft experiment showed that increased miR‐206 could effectively inhibit the tumorigenesis of TC cells. Our study showed that miR‐206 negatively regulated cell activities of proliferation, invasion, and migration in TC via suppressing RAP1B expression, suggesting that miR‐206 exerts a vital role in TC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

miR‐206 inhibits thyroid cancer proliferation and invasion by targeting RAP1B

Wang

et al. 2019

J of Cellular Biochemistry

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“…While both SNF5 / snf5 and CYR1 / cyr1 mutants had no perceptible fitness defect, the SNF5 / snf5 CYR1 / cyr1 strain exhibited a growth defect similar to that of snf5 / snf5, suggesting that Snf5 and the adenylyl cyclase Cyr1 operate on the same pathway ( Figure 7D ). Intriguingly, even if Cyr1 is a key component and an effector of Ras1 pathway [49], SNF5 did not interact genetically with RAS1 . Previous study had shown that C. albicans filamentation in response to carbon dioxide depends on Cyr1, but not on Ras1, suggesting that Cyr1 controls specific functions that are independent from the Ras pathway [50,51].…”

Section: Resultsmentioning

confidence: 99%

“…In accordance with this, mutants of SWI/SNF subunits that exhibited metabolic flexibility defect in our study such as snf6 and snf5 or swi1 and arp9 belong to the same functional sub-complexes in the budding yeast. Alternatively, differential requirement of SWI/SNF subunit in C. albicans could be explained by the fact that deleting certain subunits might led to a non-functional aberrant complex that remains attached to its target promoters [58] and prevents redundant chromatin remodelling complex such as RSC to bind DNA and consequently compensates loss of SWI/SNF chromatin remodelling activity [49,50,51]. Accordingly, in S. cerevisiae , loss of Snf5 did not affect Snf2 occupancy to gene promoters and resulted in an aberrant SWI/SNF complex that functions as a dominant negative mutation by blocking recruitment of other redundant compensating chromatin remodelers [60].…”

Section: Discussionmentioning

confidence: 99%

A novel genetic circuitry governing hypoxic metabolic flexibility, commensalism and virulence in the fungal pathogen Candida albicans

Burgain

Pic

Markey

et al. 2019

Preprint

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Inside the human host, the pathogenic yeast Candida albicans colonizes predominantly oxygen-poor niches such as the gastrointestinal and vaginal tracts, but also oxygen-rich environments such as cutaneous epithelial cells and oral mucosa. This suppleness requires an effective mechanism to reprogram reversibly the primary metabolism in response to oxygen variation. Here, we have uncovered that Snf5, a subunit of SWI/SNF chromatin remodeling complex, is a major transcriptional regulator that links oxygen status to the metabolic capacity of C. albicans. Snf5 and other subunits of SWI/SNF complex were required to activate genes of alternative carbon utilization and other carbohydrates related process specifically under hypoxia. snf5 mutant exhibited an altered metabolome reflecting that SWI/SNF plays an essential role in maintaining metabolic homeostasis and carbon flux in C. albicans under hypoxia. Snf5 was necessary to activate the transcriptional program linked to both commensal and invasive growth. Accordingly, snf5 was unable to maintain its growth in the stomach, the cecum and the colon of mice. snf5 was also avirulent as it was unable to invade Galleria larvae or to cause damage to human enterocytes and murine macrophages. Among candidates of signaling pathways in which Snf5 might operate, phenotypic analysis revealed that mutants of Ras1-cAMP-PKA pathway, as well as mutants of Yak1 and Yck2 kinases exhibited a similar carbon flexibility phenotype as did snf5 under hypoxia. Genetic interaction analysis indicated that the adenylate cyclase Cyr1, a key component of the Ras1-cAMP pathway, but not Ras1, interacted genetically with Snf5. Our study yielded unprecedented insight into the oxygen-sensitive regulatory circuit that control metabolic flexibility, stress, commensalism and virulence in C. albicans.Author SummaryA critical aspect of eukaryotic cell fitness is the ability to sense and adapt to variations in oxygen concentrations in their local environment. Hypoxia leads to a substantial remodeling of cell metabolism and energy homeostasis, and thus, organisms must develop an effective regulatory mechanism to cope with oxygen depletion. Candida albicans is an opportunistic yeast that is the most prevalent human fungal pathogens. This yeast colonizes diverse niches inside the human host with contrasting carbon sources and oxygen concentrations. While hypoxia is the predominant conditions that C. albicans encounters inside most of the niches, the impact of this condition on metabolic flexibility, a major determinant of fungal virulence, was completely neglected. Here, we uncovered that the chromatin remodelling complex SWI/SNF is master regulatory circuit that links oxygen status to a broad spectrum of carbon utilization routes. Snf5 was essential for the maintenance of C. albicans as a commensal and also for the expression of its virulence. The oxygen-sensitive regulators identified in this work provide a framework to comprehensively understand the virulence of human fungal pathogens and represent a therapeutic value to fight fungal infections.

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“…In most of the pathogenic fungi, Ras pathway signaling is determined as critical virulence factor [33]. e Ras pathway signaling is involved in pathogenesis, morphological transitions, nutrient sensing and acquisition, sexual reproduction, and stress responses of fungi [34]. e results also evidenced that the pathogenicity and virulence of P. expansum was weakened, and its growth was eventually inhibited by M. guilliermondii.…”

Section: Castellote Et Al Investigated the Molecular Expression Ofmentioning

confidence: 99%

Protein Expression Profile and Transcriptome Characterization of Penicillium expansum Induced by Meyerozyma guilliermondii

Yang

Dhanasekaran

Apaliya

et al. 2020

Journal of Food Quality

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Antagonistic yeasts can inhibit fungal growth. In our previous research, Meyerozyma guilliermondii, one of the antagonistic yeasts, exhibited antagonistic activity against Penicillium expansum. However, the mechanisms, especially the molecular mechanisms of inhibiting activity of M. guilliermondii, are not clear. In this study, the protein expression profile and transcriptome characterization of P. expansum induced by M. guilliermondii were investigated. In P. expansum induced by M. guilliermondii, 66 proteins were identified as differentially expressed, among them six proteins were upregulated and 60 proteins were downregulated, which were associated with oxidative phosphorylation, ATP synthesis, basal metabolism, and response regulation. Simultaneously, a transcriptomic approach based on RNA-Seq was applied to annotate the genome of P. expansum and then studied the changes of gene expression in P. expansum treated with M. guilliermondii. The results showed that differentially expressed genes such as HEAT, Phosphoesterase, Polyketide synthase, ATPase, and Ras-association were significantly downregulated, in contrast to Cytochromes P450, Phosphatidate cytidylyltransferase, and Glutathione S-transferase, which were significantly upregulated. Interestingly, the downregulated differentially expressed proteins and genes have a corresponding relationship; these results revealed that these proteins and genes were important in the growth of P. expansum treated with M. guilliermondii.

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Multiple roles and diverse regulation of the Ras/cAMP/protein kinase A pathway in Candida albicans

Cited by 76 publications

References 98 publications

miR‐206 inhibits thyroid cancer proliferation and invasion by targeting RAP1B

miR‐206 inhibits thyroid cancer proliferation and invasion by targeting RAP1B

A novel genetic circuitry governing hypoxic metabolic flexibility, commensalism and virulence in the fungal pathogen Candida albicans

Protein Expression Profile and Transcriptome Characterization of Penicillium expansum Induced by Meyerozyma guilliermondii

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