FEMS yeast research最新文献

Although endo-lysosomal abnormalities have been recognized as a pathognomonic feature of Alzheimer's disease, the lack of druggable targets has hampered the translation from bench to bedside. This article provides an overview of the insights gained from yeast research with a focus on understudied luminal acidification mechanisms and their major impact on disease progression. The yeast-to-human discovery and validation strategy identified a "druggable" triad featuring luminal pH, sterol content, and trafficking that (dys)regulate reciprocally. Endosomal Na+/H+ exchangers (eNHE), discovered in yeast and later described in mammals, provide independent support for this pathogenic model. The brain is often the most severely affected organ in patients with eNHE mutations, and a subset is causally linked to progressive and severe neurodegeneration, demonstrating that neurons heavily rely on fine-tuning of endosomal pH. We present recent advances on the role of eNHE in ageing related neurodegenerative diseases, which has implications for pathogenesis and therapy. Future studies should unravel the broader landscape of endo-lysosomal pH in neurodegenerative diseases. Given that pharmacologic correction of luminal hyperacidification defect completely ameliorates endo-lysosomal deficits in eNHE deletion yeast, there is compelling reason to believe that efforts to target endo-lysosomal acid-base homeostasis will eventually lead to novel therapeutic approaches for neurodegenerative diseases.

Glycerol, a by-product of biodiesel production, is a versatile polyol used in various industries. Yeasts play a crucial role in converting glycerol into biofuels and value-added products, offering sustainable alternatives to chemical synthesis. This review explores glycerol metabolism in yeasts, focusing on its bioconversion into ethanol, isopropanol, lipids, organic acids, and polyols. Saccharomyces cerevisiae and Yarrowia lipolytica are prominent species for these processes, with metabolic engineering enhancing their efficiency. Ethanol production from crude glycerol, a by-product of the biodiesel industry, is cost-effective compared to traditional feedstocks, while lipid production by oleaginous yeasts supports biodiesel synthesis. Organic acids like succinic, citric, and lactic acids, along with polyols such as erythritol and mannitol, are produced through optimized pathways, achieving high yields. Crude glycerol, despite impurities, is a viable low-cost substrate, with yeast strains adapted to tolerate its contaminants. Challenges include improving strain tolerance and scaling up processes. Future research aims to refine metabolic engineering and fermentation strategies to maximize glycerol's potential as a renewable feedstock for industrial biotechnology.

The formation of hyphae is one of the most crucial virulence traits the human pathogenic fungus Candida albicans possesses. The assessment of hyphal length in response to various stimuli, such as exposure to human serum, provides valuable insights into the adaptation strategies of C. albicans to the host environment. Despite the increasing high-throughput capacity live-cell imaging and data generation, the accurate analysis of hyphal growth has remained a laborious, error-prone, and subjective manual process. We developed an analysis pipeline utilizing the open-source visual programming language Java Image Processing Pipeline (JIPipe) to overcome the limitations associated with manual analysis of hyphal growth. By comparing our automated approach with manual analysis, we refined the strategies to achieve accurate differentiation between yeast cells and hyphae. The automated method enables length measurements of individual hyphae, facilitating a time-efficient, high-throughput, and user-friendly analysis. By utilizing this JIPipe analysis approach, we obtained insights into the filamentation behavior of two C. albicans strains when exposed to human serum albumin (HSA), the most abundant protein in human serum. Our findings indicate that despite the known role of HSA in stimulating fungal growth, it reduces filamentous growth. The implementation of our automated JIPipe analysis approach for hyphal growth represents a long-awaited and time-efficient solution to meet the demand of high-throughput data generation. This tool can benefit different research areas investigating the virulence aspects of C. albicans.

Yeast-based sensors have shown great applicability for deorphanization of G protein-coupled receptors (GPCRs) and screening of ligands targeting these. A GPCR of great interest is free fatty acid 2 receptor (FFA2R), for which short-chain fatty acids such as propionate and acetate are agonists. FFA2R regulates a wide array of downstream receptor signaling pathways in both adipose tissue and immune cells and has been recognized as a promising therapeutic target, having been implicated in several metabolic and inflammatory diseases. While research aiming to identify ligands recognized by FFA2R for translational applications is ongoing, screening is complicated by the complex regulatory and cell-specific responses mediated by the receptor. To simplify screening towards identification of novel ligands, heterologous platforms are valuable tools that offer efficient identification of ligand activity in the absence of regulatory mechanisms. Here, we present a yeast-based sensor designed to evaluate G protein α i1-mediated FFA2R signaling, with an assay time of 3 h. We verify this platform towards the natural agonists, propionate and acetate, and show applicability towards evaluation of synthetic agonists, antagonists, and allosteric agonists. As such, we believe that the developed yeast strain constitutes a promising screening platform for effective evaluation of ligands acting on FFA2R.

The oleaginous yeast Rhodotorula toruloides is a promising microbial cell factory for the sustainable production of biofuels and value-added chemicals from renewable carbon sources. Unlike the conventional yeast Saccharomyces cerevisiae, R. toruloides can naturally metabolize xylose, the second most abundant sugar in lignocellulosic hydrolysates. However, its native xylose metabolism is inefficient, characterized by slow xylose uptake and accumulation of D-arabitol. Moreover, despite its phenotype, research on the enzymes involved in xylose metabolism has yet to reach a consensus. Therefore, this review provides a comprehensive analysis of the non-canonical xylose metabolism in R. toruloides, focusing on the properties of key enzymes involved in xylose metabolism. Native xylose reductase and xylitol dehydrogenase exhibit broad substrate promiscuity compared to their counterparts in the xylose-fermenting Scheffersomyces stipitis. Additionally, the absence of xylulokinase expression under xylose-utilizing conditions redirects metabolism toward D-arabitol accumulation. Consequently, D-arabitol dehydrogenases and ribulokinase play essential roles in the xylose metabolism of R. toruloides. These findings highlight the fundamental differences between R. toruloides xylose metabolism and the oxidoreductase pathways observed in other xylose-fermenting yeast, providing insights for metabolic engineering strategies to improve xylose utilization and enhance bioconversion of cellulosic hydrolysates to different bioproducts by R. toruloides.

Owing to the potential for commercialization, the recombinant production of hemoproteins has been heavily investigated. Yeast is a superior host for the synthesis of eukaryotic hemoproteins with optimal pathway to facilitate heme delivery and utilization, as well as suitable environment for the post-translational folding and modification. The efficient binding of heme is the critical determinant for the various functions of hemeproteins. Thus, many metabolic engineering strategies have been employed to modify heme synthetic pathways and balance the intracellular metabolic burden. This paper provides a comprehensive review on the improvement of heme supply, the enhancement of hemoprotein expression, and the current efforts to harmonize the synthesis of heme and the expression of protein components in yeast. These insights offer a solid foundation for the development of yeast chassis for the efficient production of high-active hemoproteins in the future.

Candida glabrata is a prominent causative agent of mucosal and disseminated human infections. Part of the success of C. glabrata as a human pathogen relies on its adherence capacity and ability to tolerate/surpass the activity of immune cells. Herein we describe the involvement of the transcription factor CgHaa1 and of its regulated genes CgAWP12, CgAWP13, CAGL0H07469 g, and CAGL0K10164 g in adherence of C. glabrata to vaginal cells in the presence of acetic acid, an organic acid usually found in this niche due to the activity of commensal bacteria. CgHaa1 and its target genes CgAWP12, CAGL0K10164 g and CAGL0E03740 g were also found to significantly increase C. glabrata-induced killing of the model wax moth Galleria mellonela, in part by modulating the interaction of the yeasts with the larvae's immune cells. Finally, we show that CgHAA1 expression reduces ingestion and subsequent killing of C. glabrata cells by THP-1 human macrophages. This demonstrated role of CgHaa1 in C. glabrata virulence and interaction with immune cells expands the biological role of this regulator positioning it (and its target genes) as a potential interesting candidate target for new therapies focused on reducing the burden of candidiasis.

Hanseniaspora species are among the most prevalent yeasts found on grapes and other fruits, with a growing role in wine fermentation due to their distinctive metabolic profiles. This review focuses on the functional divergence within the genus, particularly between the fast-evolving fruit clade and the slow-evolving fermentation clade. While species in the fruit clade often exhibit limited fermentation capacity with interesting enzymatic activity, members of the fermentation clade-especially Hanseniaspora vineae-demonstrate moderate fermentative potential and a unique ability to enhance acetylated aromatic alcohols with healthy properties. When used in mixed fermentations with Saccharomyces cerevisiae, some Hanseniaspora species contribute significantly to the production of bioactive and aromatic compounds, including tyrosol and tryptophol, and their acetate esters, benzenoids, melatonin, and other derived compounds with functional properties. The metabolic activity of Hanseniaspora is also marked by robust extracellular enzymatic functions and a rapid autolytic profile, facilitating the release of aroma precursors and phenolic compounds. This review emphasizes the role of aromatic amino acid-derived pathways-namely the phenylpyruvate, mandelate, and Ehrlich routes-in the biosynthesis of aroma-active metabolites. Overall, Hanseniaspora species represent promising non-Saccharomyces yeasts for modulating wine aroma and composition, with implications for both industrial fermentation strategies and fundamental yeast biology.

The intrinsic resistance of Candidozyma auris (C. auris) to antifungal drugs poses a major therapeutic challenge, with conventional resistance mechanisms providing only partial explanations. Sphingolipids (SLs), known for their interclade heterogeneity, play a crucial role in antifungal resistance. This study examined the SL landscape in two drug-susceptible clade II isolates, C-line and P-line, from distinct geographical origins, which were experimentally evolved to develop stable fluconazole (FLC) resistance. The progenitors displayed distinct SL profiles, P1 had higher PhytoCer and αOHPhytoCer, indicating a more active acidic SL biosynthesis branch, whereas C1 exhibited elevated αOHGlcCer, αOHCer, and LCBs, reflecting a greater role of the neutral biosynthesis branch. The principal component analysis also confirmed distinct segregation of the two progenitors. Upon evolution, P1.1 and C1.1 adaptors showed significant SL alterations. P1.1 exhibited PhytoCer enrichment, while C1.1 showed reduced αOHGlcCer alongside increased PhytoCer, dhCer, and αOHPhytoCer levels. Notably, αOHGlcCer remained unchanged in P1.1, whereas LCBs and αOHPhytoCer decreased compared to P1. Despite these lineage-specific differences between the progenitors, both evolved replicates exhibited increased PhytoCer as a common denominator like what is also observed in clinical FLC-resistant isolates. These findings highlight intraclade SL variability and suggest that specific SLs contribute to FLC resistance in C. auris.