{"title":"Modelling human proteostasis and organelle homeostasis disorders in yeast and its application in drug discovery.","authors":"Anh V Do, Memoona Zahra, Alan L Munn","doi":"10.1093/femsyr/foag023","DOIUrl":"10.1093/femsyr/foag023","url":null,"abstract":"<p><p>Disruptions in cellular homeostasis and proteostasis are central to many human diseases, yet direct mechanistic investigation in human systems remains constrained by biological complexity and ethical limitations. Therefore, researchers have turned to the use of model systems that allow the more efficient dissection of fundamental cellular processes. The unicellular yeast Saccharomyces cerevisiae has emerged as a powerful eukaryotic model for studying disorders driven by defects in homeostasis and proteostasis. The relevant processes are highly conserved in yeast, enabling precise genetic manipulation and real-time analysis of mechanisms that are difficult to study in mammalian systems. Yeast models have been deployed to study prion propagation, lysosomal enzyme trafficking, and mitochondrial dysfunction. Yeast also provides a versatile platform for drug discovery, particularly through the use of the yeast two-hybrid system and high-throughput screens. Despite an inability to recapitulate the full complexity of multicellular organisms, yeast remains an invaluable tool for investigating human diseases and for the development of therapeutics. This review highlights how yeast has uniquely advanced the understanding of human diseases including those associated with prions, lysosomal proteins, and mitochondria and can be combined with the utility of yeast in drug discovery-collectively establishing yeast as a model for studying human disorders.</p>","PeriodicalId":12290,"journal":{"name":"FEMS yeast research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13263897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148143250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi-Ching Lee, Chi-Chun Huang, Matilda McDaniel, Su-Ju Lin
{"title":"The nicotinamide mononucleotide adenylyl transferase (NMNAT/Nma1) modulates phosphate-sensing (PHO) signaling independent of its NAD+ synthesis activity in Saccharomyces cerevisiae.","authors":"Yi-Ching Lee, Chi-Chun Huang, Matilda McDaniel, Su-Ju Lin","doi":"10.1093/femsyr/foag041","DOIUrl":"10.1093/femsyr/foag041","url":null,"abstract":"<p><p>Regulation of NAD+ metabolism is interconnected with multiple nutrient-sensing pathways and cellular processes. The phosphate (Pi)-sensing (PHO) signaling pathway contributes to NAD+ degradation, and PHO-responsive genes are reciprocally regulated in a NAD+-dependent manner. In this study, we examine whether the NAD+ biosynthetic enzyme Nma1 has a direct role in modulating PHO signaling. We show that Nma1 physically interacts with Pho4, a transcription factor translocating to the nucleus to activate PHO-responsive genes during Pi depletion. Overexpression of NMA1 or its catalytically inactive variant significantly reduces Pi depletion-induced Pho4 nuclear localization and the activation of PHO-responsive genes, indicating the NAD+ synthesis activity of Nma1 is dispensable in the downregulation of PHO signaling. Interestingly, mutating the C-terminal domain of Nma1, which is required for the ATPase chaperone activity of mammalian NMNATs, fails to decrease Pho4 nuclear localization and the expression of PHO-responsive genes. Moreover, loss of Nma1 increases Pho4 nuclear localization under moderate Pi-depleted conditions, suggesting that cells lacking Nma1 are more sensitive to Pi availability alterations. These results support that Nma1 can moderate PHO activation by maintaining Pho4 in the cytoplasm. Our findings uncover a novel regulatory mechanism for PHO signaling, and this regulation may help coordinate NAD+ metabolism with Pi homeostasis.</p>","PeriodicalId":12290,"journal":{"name":"FEMS yeast research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13519963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148789982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Iron acquisition mechanisms of human skin-associated fungi.","authors":"Jiwon Jeon, Junghum Shin, Won Hee Jung","doi":"10.1093/femsyr/foag045","DOIUrl":"10.1093/femsyr/foag045","url":null,"abstract":"<p><p>Human skin presents a nutritionally restrictive environment in which iron availability is tightly controlled by epidermal iron recycling, host iron-binding proteins, and nutritional immunity. Thus, skin-associated fungi must acquire iron from limited, often host-sequestered sources. This minireview summarizes current knowledge on iron acquisition systems in the fungal taxa most consistently identified in the human skin mycobiome: Malassezia species, Candida albicans, Candida auris, Rhodotorula mucilaginosa, and dermatophytes. These fungi appear to rely on diverse strategies, including reductive iron uptake, heme and ferritin utilization, and siderophore-mediated iron scavenging. However, our mechanistic understanding differs greatly among species. In C. albicans, several uptake systems have been characterized, but their direct roles in cutaneous colonization versus invasive disease remain unclear. In C. auris, persistent skin colonization is a critical biological feature, but iron sources and uptake pathways supporting its survival, as well as how they intersect with its notorious antifungal resistance, remain largely unresolved. Rhodotorula mucilaginosa and dermatophytes employ siderophore-associated iron acquisition, and yet the relevant transporters and regulatory mechanisms remain poorly characterized. Most notably, despite Malassezia's dominance in the human skin mycobiome and its uncertain status as commensal, pathogen, or both, its iron acquisition strategies remain almost completely unexplored at the functional level. Understanding how skin-associated fungi compete for and acquire iron in the cutaneous environment will provide important insights into fungal commensalism, niche adaptation, and the pathogenic transition.</p>","PeriodicalId":12290,"journal":{"name":"FEMS yeast research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Conserved and rewired MAPK networks in human fungal pathogens.","authors":"Yu-Byeong Jang, Yong-Sun Bahn","doi":"10.1093/femsyr/foag051","DOIUrl":"10.1093/femsyr/foag051","url":null,"abstract":"<p><p>Mitogen-activated protein kinase (MAPK) cascades are among the most ancient and evolutionarily conserved signalling modules in eukaryotes, translating extracellular cues into adaptive transcriptional and metabolic outputs through a hierarchical three-tier kinase architecture. In yeasts, these pathways control osmotic and oxidative stress adaptation, mating, morphogenesis, and cell wall remodelling, while in fungal pathogens they have been adapted to support virulence-factor production, host adaptation, and antifungal tolerance. Here, we summarise the current understanding of MAPK signalling in the budding model yeast Saccharomyces cerevisiae, which serves throughout as a reference template, and in four human-pathogenic fungi that span the fungal kingdom-the ascomycetous yeast Candida albicans, the emerging multidrug-resistant pathogen Candidozyma (formerly Candida) auris, the filamentous mould Aspergillus fumigatus, and the basidiomycetous yeast Cryptococcus neoformans-emphasising how a conserved kinase framework has been functionally diversified to meet species-specific demands. We focus on the MAPK signalling system of C. neoformans, which is characterised by five MAPK homologues arising from paralogue retention and pervasive pathway crosstalk. We further discuss how recent systematic genetic dissection is prompting a reassessment of MAPK redundancy and network plasticity. Finally, we consider how the divergence between fungal and host MAPK signalling defines new conceptual and therapeutic directions in medical mycology.</p>","PeriodicalId":12290,"journal":{"name":"FEMS yeast research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13618441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ronald Alexander Marr, Pablo Cartes, Brendan Cook, Vivien Measday
{"title":"Evaluating Canadian yeast strains for novel new-make spirit applications.","authors":"Ronald Alexander Marr, Pablo Cartes, Brendan Cook, Vivien Measday","doi":"10.1093/femsyr/foag005","DOIUrl":"10.1093/femsyr/foag005","url":null,"abstract":"<p><p>Whisky is an alcoholic beverage derived from fermented grain mash that is distilled into 'new make spirit' before maturing in barrels. While most research on whisky innovation has focused on raw materials or maturation, yeast strain selection remains a relatively underexplored avenue for product diversification. Here, we evaluated yeast diversity for whisky production by screening 110 strains sourced from Canadian vineyards for maltose utilization followed by assessing 29 candidate strains in malt extract fermentations. Seven strains representing distinct genetic backgrounds were advanced to pilot-scale fermentations, including a commercial whisky control strain of Saccharomyces cerevisiae, four other S. cerevisiae strains, one Torulaspora delbrueckii strain, and one Saccharomyces uvarum strain isolated from British Columbia wine fermentations. Fermentation performance was assessed via high performance liquid chromatography, and volatile organic compounds in new make spirits were profiled using headspace solid-phase microextraction-gas chromatography-mass spectrometry. All strains completed fermentation except T. delbrueckii, despite undergoing sequential inoculation with a commercial whisky strain. Fermentations with non-S. cerevisiae yeast strains contained elevated levels of glycerol and organic acids. Volatile organic compounds analysis identified 43 compounds, revealing strain-dependent aroma diversity. Notably, S. uvarum P01E08 was enriched in 2-phenylethyl octanoate, phenylethyl alcohol, and phenylethyl acetate. These findings highlight diverse regional yeast selection as a viable strategy to expand whisky sensory diversity.</p>","PeriodicalId":12290,"journal":{"name":"FEMS yeast research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12884848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146092487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Thiol groups are determinant for overcoming acetic acid and pH stress in wine and beer fermentation-derived Saccharomyces cerevisiae strains.","authors":"Anahit Shirvanyan, Angela Primavera, Nicoletta Guaragnella, Rodrigo Ledesma-Amaro, Karen Trchounian","doi":"10.1093/femsyr/foag004","DOIUrl":"10.1093/femsyr/foag004","url":null,"abstract":"<p><p>Acetic acid (AA), a natural by-product of ethanol fermentation in yeast cells, is widely present in lignocellulosic hydrolysate as a fermentation inhibitor. Thus, gaining insight into the molecular mechanisms of AA tolerance in yeast is particularly relevant for industrial applications. This study investigates the response to AA stress in two Saccharomyces cerevisiae strains (ATCC 9804 and ATCC 13007) during different metabolic states (fermentation, respiro-fermentation, and respiration) and external pH levels (3․0 and 4.5). The results show that AA reduces the viability of both strains in a dosage-dependent manner. Moreover, ATCC 13007 is more sensitive to AA stress compared to ATCC 9804. Respiratory metabolism and higher pH correlate with better resistance to AA stress. Catalase activity was observed to increase by 1.5-6-fold under AA stress conditions, in accordance with changes in yeast thiol group content and growth. The influence of AA stress is reactive oxygen species-dependent, and redox balance regulation was found to increase the robustness of S. cerevisiae ATCC 13007 to AA by 2-fold. The study reveals valuable insights into yeast adaptation to stress conditions, contributing to the development of robust yeast strain construction for high-yield biomass and chemicals production.</p>","PeriodicalId":12290,"journal":{"name":"FEMS yeast research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12884846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A CRISPR/Cas9-based genome-editing platform enabling efficient and precise gene replacement in Lipomyces starkeyi.","authors":"Rikako Sato, Kaito Maruyama, Satoshi Ara, Masayuki Shibata, Yosuke Shida, Wataru Ogasawara, Harutake Yamazaki, Hiroaki Takaku","doi":"10.1093/femsyr/foag014","DOIUrl":"10.1093/femsyr/foag014","url":null,"abstract":"<p><p>Lipomyces starkeyi is a promising oleaginous yeast with industrial potential. However, its genome engineering remains constrained by low gene-targeting efficiency and the requirement for long homologous regions. Herein, we established a CRISPR/Cas9 genome-editing platform for L. starkeyi by expressing codon-optimized Streptococcus pyogenes Cas9 fused to an SV40 nuclear localization signal. Furthermore, in vitro-transcribed single-guide RNAs (sgRNAs) were directly delivered into the host, eliminating the need for endogenous RNA polymerase III-dependent sgRNA expression. CRISPR/Cas9 activity was validated using a codon-optimized Aequorea coerulescens GFP reporter. Cas9-induced frameshift mutations caused GFP disruption, leading to fluorescence loss. Gene replacement at the LsURA3 locus was evaluated using donor constructs with homologous regions ranging from 50-3000 bp. In a Cas9-expressing wild-type background, precise gene replacement was dependent on homology arm length, increasing from 36% with 50-bp arms to 80% with 3000-bp arms. Notably, in a Cas9-expressing Δlslig4 strain with suppressed non-homologous end joining (NHEJ), precise gene replacement was achieved with 100% accuracy using 50-bp homology arms under CRISPR/Cas9-dependent conditions. Together, these results demonstrate that a Pol III-independent CRISPR/Cas9 system combined with NHEJ suppression enables precise genome editing in L. starkeyi, providing a foundation for functional genomics and metabolic engineering.</p>","PeriodicalId":12290,"journal":{"name":"FEMS yeast research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13159722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Establishment of a protoplast transformation method for the oleaginous yeast Rhodotorula toruloides.","authors":"Xin Chen, Verena Siewers","doi":"10.1093/femsyr/foag028","DOIUrl":"10.1093/femsyr/foag028","url":null,"abstract":"<p><p>Rhodotorula toruloides is an oleaginous yeast with great potential for chemical and biofuel production, due to its ability to utilize lignocellulosic biomass and to produce high levels of carotenoids and storage lipids. However, its broader application in biotechnology has been limited by the lack of efficient genetic transformation methods. Although protoplast transformation is wildly used in fungal systems, it has remained largely unexplored in R. toruloides. In this study, we established a protoplast transformation protocol using linear DNA fragments and R. toruloides strain BOT-A2, a recently isolated strain with high lipid-producing potential. We first confirmed that BOT-A2 is a MAT A2 haploid strain. We then produced a β-1,3-glucomannanase (Man5C) that effectively digests the R. toruloides cell wall. Key parameters affecting transformation efficiency were systematically optimized, including the Man5C digestion conditions, antibiotic selection pressure, cell growth phase, protoplast yield and viability, PEG formulation, calcium ion concentration, and regeneration conditions. Using the optimized protocol, we successfully transformed BOT-A2 with three heterologous resistance cassettes (hygromycin R, bleomycin, and G418) yielding 190, 226, and 244 transformants per µg of DNA, respectively. This method provides a platform for genetic manipulation and is expected to facilitate both fundamental research and metabolic engineering in R. toruloides BOT-A2.</p>","PeriodicalId":12290,"journal":{"name":"FEMS yeast research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13343485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Yeasts in the gastrointestinal tract.","authors":"Katherine D Mueller, Soo Chan Lee","doi":"10.1093/femsyr/foag029","DOIUrl":"10.1093/femsyr/foag029","url":null,"abstract":"<p><p>The human gastrointestinal (GI) microbiota has come to be recognized as a modulator of health. However, interest in fungi and their function as members of the microbiota has lagged behind interest in bacteria. Despite the lack of historical interest, fungi are prevalent in the human GI tract and have an outsized impact on host immunity. In this review, we aim to examine the associations and potential impact of yeasts on human health outcomes. This review summarizes the associations between yeasts and inflammatory bowel diseases, highlights the predictive service that yeasts may provide in cancer therapy, and explores the possibility of yeasts as therapeutic effectors. There remain significant challenges in data analysis and identifying the relevance of fungal morphology; however, the pathways for clinical translation open to yeasts in the GI tract make these challenges worth overcoming.</p>","PeriodicalId":12290,"journal":{"name":"FEMS yeast research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13355319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Saccharomyces cerevisiae as a model for mammalian diseases.","authors":"Evelyn Sattlegger, Anja H Schiemann","doi":"10.1093/femsyr/foag013","DOIUrl":"10.1093/femsyr/foag013","url":null,"abstract":"<p><p>For many human diseases and disorders, the underlying molecular mechanism often remains poorly understood, limiting progress in developing effective targeted therapies and diagnostic tools. To fill this gap in knowledge, surrogate systems are required that faithfully recapitulate in vivo biology, as direct experimentation in humans is not feasible. Most mammalian cell lines are immortalized and genetically altered, making them limited representatives of normal physiological states. Animal models are costly, labour-intensive, and raise ethical concerns. On the other hand, the eukaryote Saccharomyces cerevisiae is a powerful model system for deciphering biological mechanisms and diseases in exquisite molecular detail. Fundamental cellular and molecular processes are highly conserved between yeast and humans. Yeast can be diploid, or haploid where the effect of a genetic change is not masked by the intact second allele. It is inexpensive to handle, grows rapidly, and is highly amenable to manipulation at the genetic, molecular, biochemical, and cellular level. Moreover, an ever-growing array of advanced technologies, protocols, yeast collections and libraries, and databases is available. This review highlights examples in which yeast has advanced our understanding of biological processes and diseases, facilitated drug development, and informed therapeutic interventions, demonstrating that it remains highly relevant in modern biomedical research.</p>","PeriodicalId":12290,"journal":{"name":"FEMS yeast research","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13094546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}