Progress in molecular and subcellular biology最新文献

Zygosaccharomyces bailii and two closely related species, Z. parabailii and Z. pseudobailii ("Z. bailii species complex", "Z. bailii sensu lato" or simply "Z. bailii (s.l.)"), are frequently implicated in the spoilage of acidified preserved foods and beverages due to their tolerance to very high concentrations of weak acids used as food preservatives. The recent sequencing and annotation of these species' genomes have clarified their genomic organization and phylogenetic relationship, which includes events of interspecies hybridization. Mechanistic insights into their adaptation and tolerance to weak acids (e.g., acetic and lactic acids) are also being revealed. Moreover, the potential of Z. bailii (s.l.) to be used in industrial biotechnological processes as interesting cell factories for the production of organic acids, reduction of the ethanol content, increase of alcoholic beverages aroma complexity, as well as of genetic source for increasing weak acid resistance in yeast, is currently being considered. This chapter includes taxonomical, ecological, physiological, and biochemical aspects of Z. bailii (s.l.). The focus is on the exploitation of physiological genomics approaches that are providing the indispensable holistic knowledge to guide the effective design of strategies to overcome food spoilage or the rational exploitation of these yeasts as promising cell factories.

Drug resistance mechanisms in the commensal human pathogen Candida albicans are continually evolving. Over time, Candida species have implemented diverse strategies to vanquish the effects of various classes of drugs, thereby emanating as a serious life threat. Apart from the repertoire of well-established strategies, which predominantly comprise permeability constraints, increased drug efflux or compromised drug import, alteration, overexpression of drug targets, and chromosome duplication, C. albicans has evolved novel regulatory mechanisms of drug resistance. For instance, recent evidences point to newer circuitry involving different mediators of the stress-responsive machinery of oxidative, osmotic, thermal, nitrosative, and nutrient limitation, which contribute to the emergence of drug resistance. Contemporary advances in genome-wide studies of transcription factors, for instance, the Zn₂Cys₆ transcription factors, TAC1 (transcriptional activator of CDR) in Candida albicans, or YRR1 in yeast have made it feasible to dissect their involvement for the elucidation of unexplored regulatory network of drug resistance. The coordination of implementers of the conventional and nonconventional drug resistance strategies provides robustness to this commensal human pathogen. In this review, we shed light not only on the established strategies of antifungal resistance but also discuss emerging cellular circuitry governing drug resistance of this human pathogen.

Candida glabrata is the second most common cause of candidemia worldwide and its prevalence has continuously increased over the last decades. C. glabrata infections are especially worrisome in immunocompromised patients, resulting in serious systemic infections, associated to high mortality rates. Intrinsic resistance to azole antifungals, widely used drugs in the clinical setting, and the ability to efficiently colonize the human host and medical devices, withstanding stress imposed by the immune system, are thought to underlie the emergence of C. glabrata. There is a clear clinical need to understand drug and stress resistance in C. glabrata. The increasing prevalence of multidrug resistant isolates needs to be addressed in order to overcome the decrease of viable therapeutic strategies and find new therapeutic targets. Likewise, the understanding of the mechanisms underlying its impressive ability thrive under oxidative, nitrosative, acidic and metabolic stresses, is crucial to design drugs that target these pathogenesis features. The study of the underlying mechanisms that translate C. glabrata plasticity and its competence to evade the immune system, as well as survive host stresses to establish infection, will benefit from extensive scrutiny. This chapter provides a review on the contribution of genome-wide studies to uncover clinically relevant drug resistance and stress response mechanisms in the human pathogenic yeast C. glabrata.

High rate of reported cases of infections in humans caused by fungal pathogens pose serious concern. Potentially these commensal fungi remain harmless to the healthy individuals but can cause severe systemic infection in patients with compromised immune system. Effective drug remedies against these infections are rather limited. Moreover, frequently encountered multidrug resistance poses an additional challenge to search for alternate and novel targets. Notably, imbalances in lipid homeostasis which impact drug susceptibility of Candida albicans cells do provide clues of novel therapeutic strategies. Sphingolipids (SPHs) are unique components of Candida cells, hence are actively exploited as potential drug targets. In addition, recent research has uncovered that several SPH intermediates and of other lipids as well, govern cell signaling and virulence of C. albicans. In this chapter, we highlight the role of lipids in the physiology of Candida, particularly focusing on their roles in the development of drug resistance. Considering the importance of lipids, the article also highlights recent high-throughput analytical tools and methodologies, which are being employed in our understanding of structures, biosynthesis, and roles of lipids in fungal pathogens.

The contemporary approach of physiological genomics is vital in providing the indispensable holistic understanding of the complexity of the molecular targets, signalling pathways and molecular mechanisms underlying the responses and tolerance to stress, a topic of paramount importance in biology and biotechnology. This chapter focuses on the toxicity and tolerance to relevant stresses in the cell factory and eukaryotic model yeast Saccharomyces cerevisiae. Emphasis is given to the function and regulation of multidrug/multixenobiotic resistance (MDR/MXR) transporters. Although these transporters have been considered drug/xenobiotic efflux pumps, the exact mechanism of their involvement in multistress resistance is still open to debate, as highlighted in this chapter. Given the conservation of transport mechanisms from S. cerevisiae to less accessible eukaryotes such as plants, this chapter also provides a proof of concept that validates the relevance of the exploitation of the experimental yeast model to uncover the function of novel MDR/MXR transporters in the plant model Arabidopsis thaliana. This knowledge can be explored for guiding the rational design of more robust yeast strains with improved performance for industrial biotechnology, for overcoming and controlling the deleterious activities of spoiling yeasts in the food industry, for developing efficient strategies to improve crop productivity in agricultural biotechnology.

Understanding genotype-phenotype dependency is a universal aim for all life sciences. While the complete genotype-phenotype relations remain challenging to resolve, metabolic phenotypes are moving within the reach through genome-scale metabolic model simulations. Genome-scale metabolic models are available for commonly investigated yeasts, such as model eukaryote and domesticated fermentation species Saccharomyces cerevisiae, and automatic reconstruction methods facilitate obtaining models for any sequenced species. The models allow for investigating genotype-phenotype relations through simulations simultaneously considering the effects of nutrient availability, and redox and energy homeostasis in cells. Genome-scale models also offer frameworks for omics data integration to help to uncover how the translation of genotypes to the apparent phenotypes is regulated at different levels. In this chapter, we provide an overview of the yeast genome-scale metabolic models and the simulation approaches for using these models to interrogate genotype-phenotype relations. We review the methodological approaches according to the underlying biological reasoning in order to inspire formulating novel questions and applications that the genome-scale metabolic models could contribute to. Finally, we discuss current challenges and opportunities in the genome-scale metabolic model simulations.

Ageing is a complex and multifactorial process driven by genetic, environmental and stochastic factors that lead to the progressive decline of biological systems. Mechanisms of ageing have been extensively investigated in various model organisms and systems generating fundamental advances. Notably, studies on yeast ageing models have made numerous and relevant contributions to the progress in the field. Different longevity factors and pathways identified in yeast have then been shown to regulate molecular ageing in invertebrate and mammalian models. Currently the best candidates for anti-ageing drugs such as spermidine and resveratrol or anti-ageing interventions such as caloric restriction were first identified and explored in yeast. Yeasts have also been instrumental as models to study the cellular and molecular effects of proteins associated with age-related diseases such as Parkinson's, Huntington's or Alzheimer's diseases. In this chapter, a review of the advances on ageing and age-related diseases research in yeast models will be made. Particular focus will be placed on key longevity factors, ageing hallmarks and interventions that slow ageing, both yeast-specific and those that seem to be conserved in multicellular organisms. Their impact on the pathogenesis of age-related diseases will be also discussed.

Lignocellulosic biomass has been widely studied as the renewable feedstock for the production of biofuels and biochemicals. Budding yeast Saccharomyces cerevisiae is commonly used as a cell factory for bioconversion of lignocellulosic biomass. However, economic bioproduction using fermentable sugars released from lignocellulosic feedstocks is still challenging. Due to impaired cell viability and fermentation performance by various inhibitors that are present in the cellulosic hydrolysates, robust yeast strains resistant to various stress environments are highly desired. Here, we summarize recent progress on yeast strain development for the production of biofuels and biochemical using lignocellulosic biomass. Genome-wide studies which have contributed to the elucidation of mechanisms of yeast stress tolerance are reviewed. Key gene targets recently identified based on multiomics analysis such as transcriptomic, proteomic, and metabolomics studies are summarized. Physiological genomic studies based on zinc sulfate supplementation are highlighted, and novel zinc-responsive genes involved in yeast stress tolerance are focused. The dependence of host genetic background of yeast stress tolerance and roles of histones and their modifications are emphasized. The development of robust yeast strains based on multiomics analysis benefits economic bioconversion of lignocellulosic biomass.

Signaling from the epidermal growth factor receptor (EGFR) elicits multiple biological responses, including cell proliferation, migration, and survival. Receptor endocytosis and trafficking are critical physiological processes that control the strength, duration, diversification, and spatial restriction of EGFR signaling through multiple mechanisms, which we review in this chapter. These mechanisms include: (i) regulation of receptor density and activation at the cell surface; (ii) concentration of receptors into distinct nascent endocytic structures; (iii) commitment of the receptor to different endocytic routes; (iv) endosomal sorting and postendocytic trafficking of the receptor through distinct pathways, and (v) recycling to restricted regions of the cell surface. We also highlight how communication between organelles controls EGFR activity along the endocytic route. Finally, we illustrate how abnormal trafficking of EGFR oncogenic mutants, as well as alterations of the endocytic machinery, contributes to aberrant EGFR signaling in cancer.