scholarly journals The Casein Kinase I Protein Cck1 Regulates Multiple Signaling Pathways and Is Essential for Cell Integrity and Fungal Virulence in Cryptococcus neoformans

2011 ◽  
Vol 10 (11) ◽  
pp. 1455-1464 ◽  
Author(s):  
Yina Wang ◽  
Tong-Bao Liu ◽  
Shyam Patel ◽  
Linghuo Jiang ◽  
Chaoyang Xue
Keyword(s):  
Signaling Pathways ◽  
Cryptococcus Neoformans ◽  
Casein Kinase ◽  
Cell Integrity ◽  
Casein Kinase I ◽  
Fungal Virulence ◽  
Content Type ◽  
Virulence Attenuation ◽  
Wide Range ◽  
Multiple Signaling

ABSTRACTCasein kinases regulate a wide range of cellular functions in eukaryotes, including phosphorylation of proteins that are substrates for degradation via the ubiquitin-proteasome system (UPS). Our previous study demonstrated that Fbp1, a component of the SCFFBP1E3 ligase complex, was essential forCryptococcusvirulence. Because theSaccharomyces cerevisiaehomolog of Fbp1, Grr1, requires casein kinase I (Yck1 and Yck2) to phosphorylate its substrates, we investigated the function of casein kinase I inCryptococcus neoformans. In this report, we identified aC. neoformanscasein kinase I protein homolog, Cck1. Similar to Fbp1, the expression of Cck1 is negatively regulated by glucose and during mating.cck1null mutants showed significant virulence attenuation in a murine systemic infection model, but Cck1 was dispensable for the development of classical virulence factors (capsule, melanin, and growth at 37°C).cck1mutants were hypersensitive to SDS treatment, indicating that Cck1 is required for cell integrity. The functional overlap between Cck1 and Fbp1 suggests that Cck1 may be required for the phosphorylation of Fbp1 substrates. Interestingly, thecck1mutant also showed increased sensitivity to osmotic stress and oxidative stress, suggesting that Cck1 regulates both cell integrity and the cellular stress response. Our results show that Cck1 regulates the phosphorylation of both Mpk1 and Hog1 mitogen-activated protein kinases (MAPKs), demonstrating that Cck1 regulates cell integrity via the Mpk1 pathway and regulates cell adaptation to stresses via the Hog1 pathway. Overall, our study revealed that Cck1 plays important roles in regulating multiple signaling pathways and is required for fungal pathogenicity.

scholarly journals Fbp1-Mediated Ubiquitin-Proteasome Pathway Controls Cryptococcus neoformans Virulence by Regulating Fungal Intracellular Growth in Macrophages

2013 ◽  
Vol 82 (2) ◽  
pp. 557-568 ◽  
Author(s):  
Tong-Bao Liu ◽  
Chaoyang Xue
Keyword(s):  
Cryptococcus Neoformans ◽  
Time Course ◽  
Ubiquitin Proteasome System ◽  
Phenotypic Analysis ◽  
Fungal Virulence ◽  
Content Type ◽  
Brain Infection ◽  
Virulence Attenuation ◽  
Ubiquitin Proteasome ◽  
F Box Protein

ABSTRACTCryptococcus neoformansis a human fungal pathogen that often causes lung and brain infections in immunocompromised patients, with a high fatality rate. Our previous results showed that an F-box protein, Fbp1, is essential forCryptococcusvirulence independent of the classical virulence factors, suggesting a novel virulence control mechanism. In this study, we show that Fbp1 is part of the ubiquitin-proteasome system, and we further investigated the mechanism of Fbp1 function during infection. Time course studies revealed that thefbp1Δ mutant causes little damage in the infected lung and that the fungal burden in the lung remains at a low but persistent level throughout infection. Thefbp1Δ mutant cannot disseminate to other organs following pulmonary infection in the murine inhalation model of cryptococcosis but still causes brain infection in a murine intravenous injection model, suggesting that the block of dissemination of thefbp1Δ mutant is due to its inability to leave the lung. Thefbp1Δ mutant showed a defect in intracellular proliferation after phagocytosis in aCryptococcus-macrophage interaction assay, which likely contributes to its virulence attenuation. To elucidate the molecular basis of the SCF(Fbp1) E3 ligase function, we analyzed potential Fbp1 substrates based on proteomic approaches combined with phenotypic analysis. One substrate, the inositol phosphosphingolipid-phospholipase C1 (Isc1), is required for fungal survival inside macrophage cells, which is consistent with the role of Fbp1 in regulatingCryptococcus-macrophage interaction and fungal virulence. Our results thus reveal a new determinant of fungal virulence that involves the posttranslational regulation of inositol sphingolipid biosynthesis.

scholarly journals Development of Protective Inflammation and Cell-Mediated Immunity against Cryptococcus neoformans after Exposure to Hyphal Mutants

mBio ◽  
2015 ◽  
Vol 6 (5) ◽  
Author(s):  
Bing Zhai ◽  
Karen L. Wozniak ◽  
Jorge Masso-Silva ◽  
Srijana Upadhyay ◽  
Camaron Hole ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Cryptococcal Meningitis ◽  
Early Stage ◽  
Future Research ◽  
Clinical Strain ◽  
Cell Mediated Immunity ◽  
Fungal Virulence ◽  
Filamentous Form ◽  
Content Type ◽  
Virulence Attenuation

ABSTRACTMorphological switch is tightly coupled with the pathogenesis of many dimorphic fungal pathogens.Cryptococcus neoformans, the major causative agent of cryptococcal meningitis, mostly presents as the yeast form but is capable of switching to the hyphal form. The filamentous form has long been associated with attenuated virulence, yet the underlying mechanism remains elusive. We previously identified the master regulator Znf2 that controls the yeast-to-hypha transition inCryptococcus. Activation of Znf2 promotes hyphal formation and abolishes fungal virulencein vivo. Here we demonstrated that the cryptococcal strain overexpressingZNF2elicited strong and yet temporally confined proinflammatory responses in the early stage of infection. In contrast, exacerbated inflammation in mice infected with the wild-type (WT) strain showed that they were unable to control the infection. Animals inoculated with this filamentousCryptococcusstrain had fewer pulmonary eosinophils and CD11c+CD11b+cells than animals inoculated with WT yeast. Moreover, mice infected with this strain developed protective Th1- or Th17-type T cell responses. These findings suggest that the virulence attenuation of the filamentous form is likely due to its elicitation of protective host responses. The antivirulence effect of Znf2 was independent of two previously identified factors downstream of Znf2. Interestingly, mucosal immunizations with high doses ofZNF2-overexpressing cells, either in the live or heat-killed form, offered 100% protection to the host from a subsequent challenge with the otherwise lethal clinical strain H99. Our results demonstrate that heat-resistant cellular components presented in cryptococcal cells with activatedZNF2elicit protective host immune responses. These findings could facilitate future research on novel immunological therapies.IMPORTANCECryptococcal meningitis is one of the leading causes of death among AIDS patients. This disease presents a severe threat to public health. The current antifungal regimens are unsatisfactory in controlling or clearing the pathogenCryptococcus neoformans. Immunotherapies and/or vaccines could be a promising approach to prevent or manage this deadly disease. However, the lack of understanding of host-pathogen interactions during cryptococcal infection greatly hampers the development of effective immunotherapies. In this study, we discovered that inoculation of cryptococcal cells with activated Znf2, a morphogenesis regulator and an antivirulence factor, could shift the host pathological Th2 responses to the protective Th1 or Th17 responses. Importantly, we discovered that vaccination with either the viable or heat-killed form ofZNF2-overexpressing cells protected animals from the otherwise lethal infection by the highly virulent clinical strain. Our study suggests that the fungal cellular component(s) of theZNF2-overexpressing strain may provide potential vaccine candidate(s) for controlling the fatal disease.

scholarly journals New Triazole NT-a9 Has Potent Antifungal Efficacy against Cryptococcus neoformans In Vitro and In Vivo

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Ren-Yi Lu ◽  
Ting-Jun-Hong Ni ◽  
Jing Wu ◽  
Lan Yan ◽  
Quan-Zhen Lv ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Pathogenic Fungi ◽  
Control Group ◽  
Survival Times ◽  
Content Type ◽  
Fungal Burden ◽  
Wide Range

ABSTRACT In the past decades, the incidence of cryptococcosis has increased dramatically, which poses a new threat to human health. However, only a few drugs are available for the treatment of cryptococcosis. Here, we described a leading compound, NT-a9, an analogue of isavuconazole, that showed strong antifungal activities in vitro and in vivo. NT-a9 showed a wide range of activities against several pathogenic fungi in vitro, including Cryptococcus neoformans, Cryptococcus gattii, Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, with MICs ranging from 0.002 to 1 μg/ml. In particular, NT-a9 exhibited excellent efficacy against C. neoformans, with a MIC as low as 0.002 μg/ml. NT-a9 treatment resulted in changes in the sterol contents in C. neoformans, similarly to fluconazole. In addition, NT-a9 possessed relatively low cytotoxicity and a high selectivity index. The in vivo efficacy of NT-a9 was assessed using a murine disseminated-cryptococcosis model. Mice were infected intravenously with 1.8 × 106 CFU of C. neoformans strain H99. In the survival study, NT-a9 significantly prolonged the survival times of mice compared with the survival times of the control group or the isavuconazole-, fluconazole-, or amphotericin B-treated groups. Of note, 4 and 8 mg/kg of body weight of NT-a9 rescued all the mice, with a survival rate of 100%. In the fungal-burden study, NT-a9 also significantly reduced the fungal burdens in brains and lungs, while fluconazole and amphotericin B only reduced the fungal burden in lungs. Taken together, these data suggested that NT-a9 is a promising antifungal candidate for the treatment of cryptococcosis infection.

scholarly journals The Role of Oxidoreductase-Like Protein Olp1 in Sexual Reproduction and Virulence of Cryptococcus neoformans

2020 ◽  
Vol 8 (11) ◽  
pp. 1730
Author(s):  
Qi-Kun Yu ◽  
Lian-Tao Han ◽  
Yu-Juan Wu ◽  
Tong-Bao Liu
Keyword(s):  
Sexual Reproduction ◽  
Cryptococcus Neoformans ◽  
Expression Patterns ◽  
Fungal Virulence ◽  
Growth Defects ◽  
Human Fungal Pathogen ◽  
Yeast Extract Peptone Dextrose ◽  
Virulence Attenuation ◽  
Protein Encoding ◽  
Fungal Mating

Cryptococcus neoformans is a basidiomycete human fungal pathogen causing lethal meningoencephalitis, mainly in immunocompromised patients. Oxidoreductases are a class of enzymes that catalyze redox, playing a crucial role in biochemical reactions. In this study, we identified one Cryptococcus oxidoreductase-like protein-encoding gene OLP1 and investigated its role in the sexual reproduction and virulence of C. neoformans. Gene expression patterns analysis showed that the OLP1 gene was expressed in each developmental stage of Cryptococcus, and the Olp1 protein was located in the cytoplasm of Cryptococcus cells. Although it produced normal major virulence factors such as melanin and capsule, the olp1Δ mutants showed growth defects on the yeast extract peptone dextrose (YPD) medium supplemented with lithium chloride (LiCl) and 5-fluorocytosine (5-FC). The fungal mating analysis showed that Olp1 is also essential for fungal sexual reproduction, as olp1Δ mutants show significant defects in hyphae growth and basidiospores production during bisexual reproduction. The fungal nuclei imaging showed that during the bilateral mating of olp1Δ mutants, the nuclei failed to undergo meiosis after fusion in the basidia, indicating that Olp1 is crucial for regulating meiosis during mating. Moreover, Olp1 was also found to be required for fungal virulence in C. neoformans, as the olp1Δ mutants showed significant virulence attenuation in a murine inhalation model. In conclusion, our results showed that the oxidoreductase-like protein Olp1 is required for both fungal sexual reproduction and virulence in C. neoformans.

scholarly journals The F-Box Protein Fbp1 Regulates Sexual Reproduction and Virulence in Cryptococcus neoformans

2011 ◽  
Vol 10 (6) ◽  
pp. 791-802 ◽  
Author(s):  
Tong-Bao Liu ◽  
Yina Wang ◽  
Sabriya Stukes ◽  
Qing Chen ◽  
Arturo Casadevall ◽  
...  
Keyword(s):  
Sexual Reproduction ◽  
Cryptococcus Neoformans ◽  
Stress Responses ◽  
Membrane Integrity ◽  
Infection Model ◽  
Calcofluor White ◽  
Fungal Virulence ◽  
Content Type ◽  
F Box Protein

ABSTRACTCryptococcus neoformansis the leading cause of fungal meningitis in immunocomprised populations. Although extensive studies have been conducted on signal transduction pathways important for fungal sexual reproduction and virulence, how fungal virulence is regulated during infection is still not understood. In this study, we identified the F-box protein Fbp1, which contains a putative F-box domain and 12 leucine-rich repeats (LRR). Althoughfbp1mutants showed normal growth and produced normal major virulence factors, such as melanin and capsule, Fbp1 was found to be essential for fungal virulence, asfbp1mutants were avirulent in a murine systemic-infection model. Fbp1 is also important for fungal sexual reproduction. Basidiospore production was blocked in bilateral mating betweenfbp1mutants, even though normal dikaryotic hyphae were observed during mating.In vitroassays of stress responses revealed thatfbp1mutants are hypersensitive to SDS, but not calcofluor white (CFW) or Congo red, indicating that Fbp1 may regulate cell membrane integrity. Fbp1 physically interacts with Skp1 homologues in bothSaccharomyces cerevisiaeandC. neoformansvia its F-box domain, suggesting it may function as part of an SCF (Skp1, Cullins, F-box proteins) E3 ligase. Overall, our study revealed that the F-box protein Fbp1 is essential for fungal sporulation and virulence inC. neoformans, which likely represents a conserved novel virulence control mechanism that involves the SCF E3 ubiquitin ligase-mediated proteolysis pathway.

scholarly journals Cell Wall Chitosan Is Necessary for Virulence in the Opportunistic Pathogen Cryptococcus neoformans

2011 ◽  
Vol 10 (9) ◽  
pp. 1264-1268 ◽  
Author(s):  
Lorina G. Baker ◽  
Charles A. Specht ◽  
Jennifer K. Lodge
Keyword(s):  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Slow Growth ◽  
Opportunistic Pathogen ◽  
Mammalian Host ◽  
Cell Integrity ◽  
Content Type ◽  
Opportunistic Fungal Pathogen ◽  
Chitin And Chitosan

ABSTRACTCryptococcus neoformansis an opportunistic fungal pathogen that causes meningoencephalitis. Its cell wall is composed of glucans, proteins, chitin, and chitosan. Multiple genetic approaches have defined a chitosan-deficient syndrome that includes slow growth and decreased cell integrity. Here we demonstrate chitosan is necessary for virulence and persistence in the mammalian host.

scholarly journals Role of an Expanded Inositol Transporter Repertoire in Cryptococcus neoformans Sexual Reproduction and Virulence

mBio ◽  
2010 ◽  
Vol 1 (1) ◽  
Author(s):  
Chaoyang Xue ◽  
Tongbao Liu ◽  
Lydia Chen ◽  
Wenjun Li ◽  
Iris Liu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Gene Family ◽  
Sexual Reproduction ◽  
Cryptococcus Neoformans ◽  
Yeast Cells ◽  
Sexual Cycle ◽  
Fungal Virulence ◽  
Content Type ◽  
Fungal Meningitis

ABSTRACTCryptococcus neoformansandCryptococcus gattiiare globally distributed human fungal pathogens and the leading causes of fungal meningitis. Recent studies reveal thatmyo-inositol is an important factor for fungal sexual reproduction. ThatC. neoformanscan utilizemyo-inositol as a sole carbon source and the existence of abundant inositol in the human central nervous system suggest that inositol is important forCryptococcusdevelopment and virulence. In accord with this central importance of inositol, an expandedmyo-inositol transporter (ITR) gene family has been identified inCryptococcus. This gene family contains two phylogenetically distinct groups, with a total of 10 or more members inC. neoformansand at least six members in the sibling speciesC. gattii. These inositol transporter genes are differentially expressed under inositol-inducing conditions based on quantitative real-time PCR analyses. Expression ofITRgenes in aSaccharomyces cerevisiaeitr1 itr2mutant lacking inositol transport can complement the slow-growth phenotype of this strain, confirming thatITRgenes arebona fideinositol transporters. Gene mutagenesis studies reveal that the Itr1 and Itr1A transporters are important formyo-inositol stimulation of mating and that functional redundancies among themyo-inositol transporters likely exist. Deletion of the inositol 1-phosphate synthase geneINO1in anitr1oritr1amutant background compromised virulence in a murine inhalation model, indicating the importance of inositol sensing and acquisition for fungal infectivity. Our study provides a platform for further understanding the roles of inositol in fungal physiology and virulence.IMPORTANCECryptococcus neoformansis an AIDS-associated human fungal pathogen that causes over 1 million cases of meningitis annually and is the leading cause of fungal meningitis in immunosuppressed patients. The initial cryptococcal infection is caused predominantly via inhalation of sexual spores or desiccated yeast cells from the environment. How this fungus completes its sexual cycle and produces infectious spores in nature and why it frequently infects the central nervous system to cause fatal meningitis are critical questions that remain to be understood. In this study, we demonstrate that inositol acquisition is important not only for fungal sexual reproduction but also for fungal virulence. We identified an expanded inositol transporter gene family that contains over 10 members, important for both fungal sexual reproduction and virulence. Our work contributes to our understanding of how fungi respond to the environmental inositol availability and its impact on sexual reproduction and virulence.

scholarly journals Fungal Virulence in a Lepidopteran Model Is an Emergent Property with Deterministic Features

mBio ◽  
2013 ◽  
Vol 4 (3) ◽  
Author(s):  
Monica A. Garcia-Solache ◽  
David Izquierdo-Garcia ◽  
Cameron Smith ◽  
Aviv Bergman ◽  
Arturo Casadevall
Keyword(s):  
Cryptococcus Neoformans ◽  
Virulence Factors ◽  
Galleria Mellonella ◽  
Emergent Property ◽  
Deterministic System ◽  
Pathogenic Potential ◽  
Fungal Virulence ◽  
Content Type ◽  
Cryptococcal Infection ◽  
Predictable Pattern

ABSTRACTVirulence has been proposed to be an emergent property, which by definition implies that it is not reducible to its components, but this application of a philosophical concept to the host-microbe interaction has not been experimentally tested. The goals of our study were to analyze the correlation of the phenotype with the ability to cause disease and to determine the dynamics of an experimental cryptococcal infection inGalleria mellonellaandAcanthamoeba castellanii. By studying the outcome of infection as host death, we showed that the dynamics of virulence in theG. mellonella/Cryptococcus neoformansinteraction follow a predictable pattern. We also found that the experimental temperature and not the presence of virulence factors was a critical parameter defining the pathogenic potential of cryptococcal species. Our results established that cryptococcal species not considered pathogenic could be pathogens given suitable conditions. Our results support the idea that virulence is an emergent property that cannot be easily predicted by a reductionist approach and yet it behaves as a deterministic system in a lepidopteran cryptococcal infection. These findings provide a road map for evaluating whether host-microbe interactions in other systems are chaotic, deterministic, or stochastic, including those with public health importance.IMPORTANCEVirulence is a complex phenotype that cannot be easily studied by analyzing its individual components in isolation. By studying the outcome of infection as the death of the host, we found that a given microbial phenotype does not necessarily correlate with its ability to cause disease and that the presence of so-called virulence factors does not predict pathogenicity, consistent with the notion that virulence is an emergent property. This paper reports that the dynamics of virulence inGalleria mellonellalarvae infected with the fungusCryptococcus neoformansfollows a predictable pattern. Establishing that virulence is an emergent property is important because it implies that it is not reducible to its components, and consequently, this phenomenon needs to be studied by a holistic approach.

scholarly journals IP7-SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Desmarini Desmarini ◽  
Sophie Lev ◽  
David Furkert ◽  
Ben Crossett ◽  
Adolfo Saiardi ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Cdk Inhibitor ◽  
Fungal Virulence ◽  
Content Type ◽  
Inositol Pyrophosphate ◽  
Pho Pathway ◽  
Mouse Infection ◽  
Pathway Activation ◽  
Pathway Regulation

ABSTRACT In the human-pathogenic fungus Cryptococcus neoformans, the inositol polyphosphate signaling pathway is critical for virulence. We recently demonstrated the key role of the inositol pyrophosphate IP7 (isomer 5-PP-IP5) in driving fungal virulence; however, the mechanism of action remains elusive. Using genetic and biochemical approaches, and mouse infection models, we show that IP7 synthesized by Kcs1 regulates fungal virulence by binding to a conserved lysine surface cluster in the SPX domain of Pho81. Pho81 is the cyclin-dependent kinase (CDK) inhibitor of the phosphate signaling (PHO) pathway. We also provide novel mechanistic insight into the role of IP7 in PHO pathway regulation by demonstrating that IP7 functions as an intermolecular “glue” to stabilize Pho81 association with Pho85/Pho80 and, hence, promote PHO pathway activation and phosphate acquisition. Blocking IP7-Pho81 interaction using site-directed mutagenesis led to a dramatic loss of fungal virulence in a mouse infection model, and the effect was similar to that observed following PHO81 gene deletion, highlighting the key importance of Pho81 in fungal virulence. Furthermore, our findings provide additional evidence of evolutionary divergence in PHO pathway regulation in fungi by demonstrating that IP7 isomers have evolved different roles in PHO pathway control in C. neoformans and nonpathogenic yeast. IMPORTANCE Invasive fungal diseases pose a serious threat to human health globally with >1.5 million deaths occurring annually, 180,000 of which are attributable to the AIDS-related pathogen, Cryptococcus neoformans. Here, we demonstrate that interaction of the inositol pyrophosphate, IP7, with the CDK inhibitor protein, Pho81, is instrumental in promoting fungal virulence. IP7-Pho81 interaction stabilizes Pho81 association with other CDK complex components to promote PHO pathway activation and phosphate acquisition. Our data demonstrating that blocking IP7-Pho81 interaction or preventing Pho81 production leads to a dramatic loss in fungal virulence, coupled with Pho81 having no homologue in humans, highlights Pho81 function as a potential target for the development of urgently needed antifungal drugs.

scholarly journals Casein Kinase I Isoform Hrr25 Is a Negative Regulator of Haa1 in the Weak Acid Stress Response Pathway in Saccharomyces cerevisiae

2017 ◽  
Vol 83 (13) ◽  
Author(s):  
Morgan E. Collins ◽  
Joshua J. Black ◽  
Zhengchang Liu
Keyword(s):  
Acetic Acid ◽  
Target Genes ◽  
Acid Stress ◽  
Weak Acid ◽  
Casein Kinase ◽  
Negative Regulator ◽  
Weak Acids ◽  
Casein Kinase I ◽  
Content Type ◽  
Weak Acid Stress

ABSTRACT Haa1 is a transcription factor that adapts Saccharomyces cerevisiae cells to weak organic acid stresses by activating the expression of various genes. Many of these genes encode membrane proteins, such as TPO2 and YRO2. How Haa1 is activated by weak acids is not clear. Here, we show that casein kinase I isoform Hrr25 is an important negative regulator of Haa1. Haa1 is known to be multiply phosphorylated. We found that mutations in HRR25 lead to reduced Haa1 phosphorylation and increased expression of Haa1 target genes and that Hrr25 interacts with Haa1. The other three casein kinase I isoforms, Yck1, Yck2, and Yck3, do not seem to play critical roles in Haa1 regulation. Hrr25 has a 200-residue C-terminal region, including a proline- and glutamine-rich domain. Our data suggest that the C-terminal region of Hrr25 is required for normal inhibition of expression of Haa1 target genes TPO2 and YRO2 and is important for cell growth but is not required for cell morphogenesis. We propose that Hrr25 is an important regulator of cellular adaptation to weak acid stress by inhibiting Haa1 through phosphorylation. IMPORTANCE Our study has revealed the casein kinase I protein Hrr25 to be a negative regulator of Haa1, a transcription factor mediating the cellular response to stresses caused by weak acids. Many studies have focused on the target genes of Haa1 and their roles in weak acid stress responses, but little has been reported on the regulatory mechanism of Haa1. Weak acids, such as acetic acid, have long been used for food preservation by slowing down the growth of fungal species, including S. cerevisiae. In the biofuel industry, acetic acid in the lignocellulosic hydrolysates limits the production of ethanol, which is undesirable. By understanding how Haa1 is regulated, we can make advances in the field of food sciences to better preserve food and engineer acetic acid-resistant strains that will increase productivity in the biofuel industry.

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