scholarly journals Roles of Three Histidine Kinase Genes in Hyphal Development and Virulence of the Pathogenic Fungus Candida albicans

1999 ◽  
Vol 181 (23) ◽  
pp. 7243-7247 ◽  
Author(s):  
Toshiko Yamada-Okabe ◽  
Toshiyuki Mio ◽  
Naomi Ono ◽  
Yuji Kashima ◽  
Mitsuaki Matsui ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Histidine Kinase ◽  
Response Regulator ◽  
Pathogenic Fungus ◽  
Signal Transmission ◽  
Systemic Candidiasis ◽  
Hyphal Development ◽  
Hyphal Formation ◽  
Transmission Pathways ◽  
Null Mutants

ABSTRACT The pathogenic fungus Candida albicans harbors three histidine kinase genes called CaSLN1, CaNIK1, and CaHK1. The disruption of any one of these three genes impaired the hyphal formation and attenuated the virulence of C. albicans in a mouse systemic candidiasis model. The effects of the disruption on hyphal formation and virulence were most severe in the cahk1Δ null mutants. Although the double disruption of CaSLN1 and CaNIK1 was impossible, further deletion of CaSLN1 or CaNIK1 in thecahk1Δ null mutants partially restored the serum-induced hypha-forming ability and virulence. When incubated with radiolabelled ATP, the recombinant CaSln1 and CaNik1 proteins, which contained their own kinase and response regulator domains, were autophosphorylated, whereas CaHk1p was not. These results imply that in C. albicans, CaSLN1 and CaNIK1 function upstream of CaHK1 but are in distinct signal transmission pathways.

scholarly journals Defective Hyphal Development and Avirulence Caused by a Deletion of the SSK1 Response Regulator Gene in Candida albicans

2000 ◽  
Vol 68 (2) ◽  
pp. 518-525 ◽  
Author(s):  
José Antonio Calera ◽  
Xiao-Jiong Zhao ◽  
Richard Calderone
Keyword(s):  
Candida Albicans ◽  
Nitrogen Availability ◽  
Response Regulator ◽  
Hyphal Development ◽  
Isolation And Characterization ◽  
Solid Media ◽  
Functional Homolog ◽  
Good Target ◽  
Two Component ◽  
Hyphal Formation

ABSTRACT In a previous study, we reported the isolation and characterization of the two-component response regulator SSK1 gene ofCandida albicans. This gene is a structural but not a functional homolog of the SSK1 andmcs4 + genes of Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively. In the present study, we have constructed and phenotypically characterized Δssk1 mutants of C. albicans. The results confirmed our previous observation thatCaSSK1, unlike SSK1 ormcs4 +, does not regulate cellular responses to either osmotic or oxidative stress. Instead, Δssk1 null strains showed severely reduced hyphal formation on serum agar and were totally defective in hyphal development on other solid media, such as medium 199 (pH 7.5) and Spider medium. In contrast, under conditions of low nitrogen availability on solid media, Δssk1 null strains dramatically hyperinvaded the agar. However, while forming germ tubes and hyphae in liquid media similar to those of the wild type, Δssk1 null strains flocculated in a manner similar to that of Δchk1 two-component histidine kinase mutants, which we have previously described. Finally, virulence studies indicated that SSK1 is essential for the pathogenesis ofC. albicans, suggesting that the Ssk1p response regulator could be a good target for antifungal therapy.

scholarly journals Isolation of CaSLN1 and CaNIK1, the genes for osmosensing histidine kinase homologues, from the pathogenic fungus Candida albicans

Microbiology ◽  
1998 ◽  
Vol 144 (2) ◽  
pp. 425-432 ◽  
Author(s):  
S. Nagahashi ◽  
T. Mio ◽  
N. Ono ◽  
T. Yamada-Okabe ◽  
M. Arisawa ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Histidine Kinase ◽  
Pathogenic Fungus

scholarly journals Release from Quorum-Sensing Molecules Triggers Hyphal Formation during Candida albicans Resumption of Growth

2005 ◽  
Vol 4 (7) ◽  
pp. 1203-1210 ◽  
Author(s):  
Brice Enjalbert ◽  
Malcolm Whiteway
Keyword(s):  
Candida Albicans ◽  
Quorum Sensing ◽  
Culture Medium ◽  
Pathogenic Fungus ◽  
Hyphal Growth ◽  
Growth Environment ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Hyphal Formation ◽  
Cyclin Genes

ABSTRACT Candida albicans is a pathogenic fungus able to change morphology in response to variations in its growth environment. Simple inoculation of stationary cells into fresh medium at 37°C, without any other manipulations, appears to be a powerful but transient inducer of hyphal formation; this process also plays a significant role in classical serum induction of hyphal formation. The mechanism appears to involve the release of hyphal repression caused by quorum-sensing molecules in the growth medium of stationary-phase cells, and farnesol has a strong but incomplete role in this process. We used DNA microarray technology to study both the resumption of growth of Candida albicans cells and molecular regulation involving farnesol. Maintaining farnesol in the culture medium during the resumption of growth both delays and reduces the induction of hypha-related genes yet triggers expression of genes encoding drug efflux components. The persistence of farnesol also prevents the repression of histone genes during hyphal growth and affects the expression of putative or demonstrated morphogenesis-regulating cyclin genes, such as HGC1, CLN3, and PCL2. The results suggest a model explaining the triggering of hyphae in the host based on quorum-sensing molecules.

scholarly journals Molecular basis of unidirectional information transmission in two-component systems: lessons from the DesK-DesR thermosensor

2021 ◽  
Author(s):  
Sofia Lima ◽  
Juan Blanco ◽  
Federico Olivieri ◽  
Juan Andres Imelio ◽  
Federico Carrion ◽  
...  
Keyword(s):  
Histidine Kinase ◽  
Regulatory Networks ◽  
Response Regulator ◽  
Signal Transmission ◽  
Phosphoryl Transfer ◽  
Signaling Systems ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Histidine Phosphorylation

Cellular signaling systems transmit information over long distances using allosteric transitions and/or post-translational modifications. In two-component systems the sensor histidine kinase and response regulator are wired through phosphoryl-transfer reactions, using either a uni- or bi-directional transmission mode, allowing to build rich regulatory networks. Using the thermosensor DesK-DesR two-component system from Bacillus subtilis and combining crystal structures, QM/MM calculations and integrative kinetic modeling, we uncover that: i) longer or shorter distances between the phosphoryl-acceptor and -donor residues can shift the phosphoryl-transfer equilibrium; ii) the phosphorylation-dependent dimerization of the regulator acts as a sequestering mechanism by preventing the interaction with the histidine kinase; and iii) the kinase's intrinsic conformational equilibrium makes the phosphotransferase state unlikely in the absence of histidine phosphorylation, minimizing backwards transmission. These mechanisms allow the system to control the direction of signal transmission in a very efficient way, showcasing the key role that structure-encoded allostery plays in signaling proteins to store and transmit information.

scholarly journals Functional analysis of the phospholipase C gene CaPLC1 and two unusual phospholipase C genes, CaPLC2 and CaPLC3, of Candida albicans

Microbiology ◽  
2005 ◽  
Vol 151 (10) ◽  
pp. 3381-3394 ◽  
Author(s):  
Donika Kunze ◽  
Inga Melzer ◽  
Désirée Bennett ◽  
Dominique Sanglard ◽  
Donna MacCallum ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Phospholipase C ◽  
Essential Gene ◽  
Pathogenic Fungus ◽  
Systemic Infection ◽  
Cellular Processes ◽  
Solid Media ◽  
Transcriptional Pattern ◽  
Human Pathogenic Fungus ◽  
Hyphal Formation

Phospholipases C are known to be important regulators of cellular processes but may also act as virulence factors of pathogenic microbes. At least three genes in the genome of the human-pathogenic fungus Candida albicans encode phospholipases with conserved phospholipase C (Plc) motifs. None of the deduced protein sequences contain N-terminal signal peptides, suggesting that these phospholipases are not secreted. In contrast to its orthologue in Sacharomyces cerevisiae, CaPLC1 seems to be an essential gene. However, a conditional mutant with reduced transcript levels of CaPLC1 had phenotypes similar to Plc1p-deficient mutants in S. cerevisiae, including reduced growth on media causing increased osmotic stress, on media with a non-glucose carbon source, or at elevated or lower temperatures, suggesting that CaPlc1p, like the Plc1p counterpart in S. cerevisiae, may be involved in multiple cellular processes. Furthermore, phenotypic screening of the heterozygous ΔCaplc1/CaPLC1 mutant showed additional defects in hyphal formation. The loss of CaPLC1 cannot be compensated by two additional PLC genes of C. albicans (CaPLC2 and CaPLC3) encoding two almost identical phospholipases C with no counterpart in S. cerevisiae but containing structural elements found in bacterial phospholipases C. Although the promoter sequences of CaPLC2 and CaPLC3 differed dramatically, the transcriptional pattern of both genes was similar. In contrast to CaPLC1, CaPLC2 and CaPLC3 are not essential. Although Caplc2/3 mutants had reduced abilities to produce hyphae on solid media, these mutants were as virulent as the wild-type in a model of systemic infection. These data suggest that C. albicans contains two different classes of phospholipases C which are involved in cellular processes but which have no specific functions in pathogenicity.

scholarly journals CO2 Signaling through the Ptc2-Ssn3 Axis Governs Sustained Hyphal Development of Candida albicans by Reducing Ume6 Phosphorylation and Degradation

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yang Lu ◽  
Chang Su ◽  
Shatarupa Ray ◽  
Yuncong Yuan ◽  
Haoping Liu
Keyword(s):  
Carbon Dioxide ◽  
Candida Albicans ◽  
Signaling Pathway ◽  
Fungal Infections ◽  
Pathogenic Fungus ◽  
Hyphal Growth ◽  
Dependent Manner ◽  
Content Type ◽  
Hyphal Development ◽  
Carbon Dioxide Levels

ABSTRACT Candida albicans is the most common cause of invasive fungal infections in humans. Its ability to sense and adapt to changing carbon dioxide levels is crucial for its pathogenesis. Carbon dioxide promotes hyphal development. The hypha-specific transcription factor Ume6 is rapidly degraded in air, but is stable under physiological CO2 and hypoxia to sustain hyphal elongation. Here, we show that Ume6 stability is regulated by two parallel E3 ubiquitin ligases, SCFGrr1 and Ubr1, in response to CO2 and O2, respectively. To uncover the CO2 signaling pathway that regulates Ume6 stability, we performed genetic screens for mutants unable to respond to CO2 for sustained filamentation. We find that the type 2C protein phosphatase Ptc2 is specifically required for CO2-induced stabilization of Ume6 and hyphal elongation. In contrast, the cyclin-dependent kinase Ssn3 is found to be required for Ume6 phosphorylation and degradation in atmospheric CO2. Furthermore, we find that Ssn3 is dephosphorylated in 5% CO2 in a Ptc2-dependent manner, whereas deletion of PTC2 has no effect on Ssn3 phosphorylation in air. Our study uncovers the Ptc2-Ssn3 axis as a new CO2 signaling pathway that controls hyphal elongation by regulating Ume6 stability in C. albicans. IMPORTANCE The capacity to sense and adapt to changing carbon dioxide levels is crucial for all organisms. In fungi, CO2 is a key determinant involved in fundamental biological processes, including growth, morphology, and virulence. In the pathogenic fungus Candida albicans, high CO2 is directly sensed by adenylyl cyclase to promote hyphal growth. However, little is known about the mechanism by which hyphal development is maintained in response to physiological levels of CO2. Here we report that a signal transduction system mediated by a phosphatase-kinase pair controls CO2-responsive Ume6 phosphorylation and stability that in turn dictate hyphal elongation. Our results unravel a new regulatory mechanism of CO2 signaling in fungi.

Candida albicans ENO1 null mutants exhibit altered drug susceptibility, hyphal formation, and virulence

2013 ◽  
Vol 51 (3) ◽  
pp. 345-351 ◽  
Author(s):  
Hui-Ching Ko ◽  
Ting-Yin Hsiao ◽  
Chiung-Tong Chen ◽  
Yun-Liang Yang
Keyword(s):  
Candida Albicans ◽  
Drug Susceptibility ◽  
Hyphal Formation ◽  
Null Mutants

scholarly journals Deletion of the Candida albicans histidine kinase gene CHK1 improves recognition by phagocytes through an increased exposure of cell wall β-1,3-glucans

Microbiology ◽  
2010 ◽  
Vol 156 (11) ◽  
pp. 3432-3444 ◽  
Author(s):  
Nina Klippel ◽  
Shuna Cui ◽  
Lothar Groebe ◽  
Ursula Bilitewski
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Histidine Kinase ◽  
Parental Strain ◽  
Antifungal Agents ◽  
Pathogenic Fungus ◽  
Immune Recognition ◽  
Histidine Kinases ◽  
Kinase Gene ◽  
Promising Target

The pathogenic fungus Candida albicans is able to cover its most potent proinflammatory cell wall molecules, the β-glucans, underneath a dense mannan layer, so that the pathogen becomes partly invisible for immune cells such as phagocytes. As the C. albicans histidine kinases Chk1p, Cos1p and CaSln1p had been reported to be involved in virulence and cell wall biosynthesis, we investigated whether deletion of the respective genes influences the activity of phagocytes against C. albicans. We found that among all histidine kinase genes, CHK1 plays a prominent role in phagocyte activation. Uptake of the deletion mutant Δchk1 as well as the acidification of Δchk1-carrying phagosomes was significantly increased compared with the parental strain. These improved activities could be correlated with an enhanced accessibility of the mutant β-1,3-glucans for immunolabelling. In addition, any inhibition of β-1,3-glucan-mediated phagocytosis resulted in a reduced uptake of Δchk1, while ingestion of the parental strain was hardly affected. Moreover, deletion of CHK1 caused an enhanced release of interleukins 6 and 10, indicating a stronger activation of the β-1,3-glucan receptor dectin-1. In conclusion, the Chk1p protein is likely to be involved in masking β-1,3-glucans from immune recognition. As there are no homologues of fungal histidine kinases in mammals, Chk1p has to be considered as a promising target for new antifungal agents.

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