Role of the Mitogen-Activated Protein Kinase Hog1p in Morphogenesis and Virulence of Candida albicans

ABSTRACT The relevance of the mitogen-activated protein (MAP) kinase Hog1p in Candida albicans was addressed through the characterization of C. albicans strains without a functional HOG1 gene. Analysis of the phenotype ofhog1 mutants under osmostressing conditions revealed that this mutant displays a set of morphological alterations as the result of a failure to complete the final stages of cytokinesis, with parallel defects in the budding pattern. Even under permissive conditions,hog1 mutants displayed a different susceptibility to some compounds such as nikkomycin Z or Congo red, which interfere with cell wall functionality. In addition, the hog1 mutant displayed a colony morphology different from that of the wild-type strain on some media which promote morphological transitions in C. albicans. We show that C. albicans hog1 mutants are derepressed in the serum-induced hyphal formation and, consistently with this behavior, that HOG1 overexpression inSaccharomyces cerevisiae represses the pseudodimorphic transition. Most interestingly, deletion of HOG1 resulted in a drastic increase in the mean survival time of systemically infected mice, supporting a role for this MAP kinase pathway in virulence of pathogenic fungi. This finding has potential implications in antifungal therapy.

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The Cek1 and Hog1 Mitogen-Activated Protein Kinases Play Complementary Roles in Cell Wall Biogenesis and Chlamydospore Formation in the Fungal Pathogen Candida albicans

Eukaryotic Cell ◽

10.1128/ec.5.2.347-358.2006 ◽

2006 ◽

Vol 5 (2) ◽

pp. 347-358 ◽

Cited By ~ 109

Author(s):

B. Eisman ◽

R. Alonso-Monge ◽

E. Román ◽

D. Arana ◽

C. Nombela ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Map Kinase ◽

Fungal Pathogen ◽

Hog Pathway ◽

Cell Wall Biogenesis ◽

Chlamydospore Formation ◽

Mitogen Activated Protein ◽

Morphological Transitions ◽

Relationship Of

ABSTRACT The Hog1 mitogen-activated protein (MAP) kinase mediates an adaptive response to both osmotic and oxidative stress in the fungal pathogen Candida albicans. This protein also participates in two distinct morphogenetic processes, namely the yeast-to-hypha transition (as a repressor) and chlamydospore formation (as an inducer). We show here that repression of filamentous growth occurs both under serum limitation and under other partially inducing conditions, such as low temperature, low pH, or nitrogen starvation. To understand the relationship of the HOG pathway to other MAP kinase cascades that also play a role in morphological transitions, we have constructed and characterized a set of double mutants in which we deleted both the HOG1 gene and other signaling elements (the CST20, CLA4, and HST7 kinases, the CPH1 and EFG1 transcription factors, and the CPP1 protein phosphatase). We also show that Hog1 prevents the yeast-to-hypha switch independent of all the elements analyzed and that the inability of the hog1 mutants to form chlamydospores is suppressed when additional elements of the CEK1 pathway (CST20 or HST7) are altered. Finally, we report that Hog1 represses the activation of the Cek1 MAP kinase under basal conditions and that Cek1 activation correlates with resistance to certain cell wall inhibitors (such as Congo red), demonstrating a role for this pathway in cell wall biogenesis.

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Role of Mitogen-Activated Protein Kinase Pathway in Prostaglandin F2α-Induced Rat Puerperal Uterine Contraction

Endocrinology ◽

10.1210/endo.138.8.5305 ◽

1997 ◽

Vol 138 (8) ◽

pp. 3103-3111 ◽

Cited By ~ 31

Author(s):

Masahide Ohmichi ◽

Koji Koike ◽

Akiko Kimura ◽

Kanji Masuhara ◽

Hiromasa Ikegami ◽

...

Keyword(s):

Map Kinase ◽

Uterine Contraction ◽

Prostaglandin F2α ◽

Mek Inhibitor ◽

Biological Action ◽

Mitogen Activated Protein Kinase ◽

Myometrial Cells ◽

Mitogen Activated Protein ◽

Kinase Pathway

Abstract In this study, prostaglandin (PG) F2α was found to activate mitogen-activated protein (MAP) kinase and MAP kinase kinase (MEK) in cultured rat puerperal uterine myometrial cells. PGF2α stimulation also led to an increase in phosphorylation of raf-1, son of sevenless (SOS), and Shc. Furthermore, we examined the mechanism by which PGF2α induced MAP kinase phosphorylation. Both pertussis toxin (10 ng/ml), which inactivates Gi/Go proteins, and expression of a peptide derived from the carboxyl terminus of the β-adrenergic receptor kinase 1 (βARK1), which specifically blocks signaling mediated by the βγ subunits of G proteins, blocked the PGF2α-induced activation of MAP kinase. Ritodrine (1 μm), which is known to relax uterine muscle contraction, attenuated PGF2α-induced tyrosine phosphorylation of MAP kinase. Moreover, to examine the role of MAP kinase pathway in uterine contraction, an inhibitor of MEK activity, PD098059, was used. Although MEK inhibitor had no effect on PGF2α-induced calcium mobilization, this inhibitor partially inhibited PGF2α-induced uterine contraction. These results provide evidence that PGF2α stimulates the MAP kinase signaling pathway in cultured rat puerperal uterine myometrial cells through Gβγ protein, suggesting that this new pathway may play an important role in the biological action of PGF2α on these cells.

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Candida albicans Cek1 Mitogen-Activated Protein Kinase Signaling Enhances Fungicidal Activity of Salivary Histatin 5

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00214-15 ◽

2015 ◽

Vol 59 (6) ◽

pp. 3460-3468 ◽

Cited By ~ 7

Author(s):

Rui Li ◽

Sumant Puri ◽

Swetha Tati ◽

Paul J. Cullen ◽

Mira Edgerton

Keyword(s):

Candida Albicans ◽

Protein Kinase ◽

Antifungal Drugs ◽

Mitogen Activated Protein Kinase ◽

Fungal Cell ◽

Content Type ◽

Histatin 5 ◽

Mitogen Activated Protein ◽

Hyphal Formation ◽

Sensor Proteins

ABSTRACTCandida albicansis a major etiological organism for oropharyngeal candidiasis (OPC), while salivary histatin 5 (Hst 5) is a human fungicidal protein that protects the oral cavity from OPC.C. albicanssenses its environment by mitogen-activated protein kinase (MAPK) activation that can also modulate the activity of some antifungal drugs, including Hst 5. We found that phosphorylation of the MAPK Cek1, induced either byN-acetylglucosamine (GlcNAc) or serum, or its constitutive activation by deletion of its phosphatase Cpp1 elevated the susceptibility ofC. albicanscells to Hst 5. Cek1 phosphorylation but not hyphal formation was needed for increased Hst 5 sensitivity. Interference with the Cek1 pathway by deletion of its head sensor proteins, Msb2 and Sho1, or by addition of secreted aspartyl protease (SAP) cleavage inhibitors, such as pepstatin A, reduced Hst 5 susceptibility under Cek1-inducing conditions. Changes in fungal cell surface glycostructures also modulated Hst 5 sensitivity, and Cek1-inducing conditions resulted in a higher uptake rate of Hst 5. These results show that there is a consistent relationship between activation of Cek1 MAPK and increased Hst 5 susceptibility inC. albicans.

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Streptococcus gordonii Modulates Candida albicans Biofilm Formation through Intergeneric Communication

Infection and Immunity ◽

10.1128/iai.00438-09 ◽

2009 ◽

Vol 77 (9) ◽

pp. 3696-3704 ◽

Cited By ~ 182

Author(s):

Caroline V. Bamford ◽

Anita d'Mello ◽

Angela H. Nobbs ◽

Lindsay C. Dutton ◽

M. Margaret Vickerman ◽

...

Keyword(s):

Candida Albicans ◽

Oral Cavity ◽

Mitogen Activated Protein Kinase ◽

Cell Contact ◽

Streptococcus Gordonii ◽

Autoinducer 2 ◽

Mitogen Activated Protein ◽

Hyphal Formation ◽

Coated Surfaces ◽

Infection Processes

ABSTRACT The fungus Candida albicans colonizes human oral cavity surfaces in conjunction with a complex microflora. C. albicans SC5314 formed biofilms on saliva-coated surfaces that in early stages of development consisted of ∼30% hyphal forms. In mixed biofilms with the oral bacterium Streptococcus gordonii DL1, hyphal development by C. albicans was enhanced so that biofilms consisted of ∼60% hyphal forms. Cell-cell contact between S. gordonii and C. albicans involved Streptococcus cell wall-anchored proteins SspA and SspB (antigen I/II family polypeptides). Repression of C. albicans hyphal filament and biofilm production by the quorum-sensing molecule farnesol was relieved by S. gordonii. The ability of a luxS mutant of S. gordonii deficient in production of autoinducer 2 to induce C. albicans hyphal formation was reduced, and this mutant suppressed farnesol inhibition of hyphal formation less effectively. Coincubation of the two microbial species led to activation of C. albicans mitogen-activated protein kinase Cek1p, inhibition of Mkc1p activation by H2O2, and enhanced activation of Hog1p by farnesol, which were direct effects of streptococci on morphogenetic signaling. These results suggest that interactions between C. albicans and S. gordonii involve physical (adherence) and chemical (diffusible) signals that influence the development of biofilm communities. Thus, bacteria may play a significant role in modulating Candida carriage and infection processes in the oral cavity.

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p38α Mitogen-activated Protein Kinase Sensitizes Cells to Apoptosis Induced by Different Stimuli

Molecular Biology of the Cell ◽

10.1091/mbc.e03-08-0592 ◽

2004 ◽

Vol 15 (2) ◽

pp. 922-933 ◽

Cited By ~ 171

Author(s):

Almudena Porras ◽

Susana Zuluaga ◽

Emma Black ◽

Amparo Valladares ◽

Alberto M. Alvarez ◽

...

Keyword(s):

Map Kinase ◽

Cell Types ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signal Regulated Kinase ◽

Survival Pathways ◽

Proapoptotic Protein ◽

Extracellular Signal ◽

Survival Pathway ◽

Mitogen Activated Protein

p38α mitogen-activated protein (MAP) kinase is a broadly expressed signaling molecule that participates in the regulation of cellular responses to stress as well as in the control of proliferation and survival of many cell types. We have used cell lines derived from p38α knockout mice to study the role of this signaling pathway in the regulation of apoptosis. Here, we show that cardiomyocytes and fibroblasts lacking p38α are more resistant to apoptosis induced by different stimuli. The reduced apoptosis of p38α-deficient cells correlates with decreased expression of the mitochondrial proapoptotic protein Bax and the apoptosis-inducing receptor Fas/CD-95. Cells lacking p38α also have increased extracellular signal-regulated kinase (ERKs) MAP kinase activity, and the up-regulation of this survival pathway seems to be at least partially responsible for the reduced levels of apoptosis in the absence of p38α. Phosphorylation of the transcription factor STAT3 on Ser-727, mediated by the extracellular signal-regulated kinase MAP kinase pathway, may contribute to the decrease in both Bax and Fas expression in p38α-/- cells. Thus, p38α seems to sensitize cells to apoptosis via both up-regulation of proapoptotic proteins and down-regulation of survival pathways.

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Functional characterization of the MKC1 gene of Candida albicans, which encodes a mitogen-activated protein kinase homolog related to cell integrity.

Molecular and Cellular Biology ◽

10.1128/mcb.15.4.2197 ◽

1995 ◽

Vol 15 (4) ◽

pp. 2197-2206 ◽

Cited By ~ 134

Author(s):

F Navarro-García ◽

M Sánchez ◽

J Pla ◽

C Nombela

Keyword(s):

Candida Albicans ◽

Map Kinase ◽

Map Kinases ◽

Functional Characterization ◽

Mitogen Activated Protein Kinase ◽

Lytic Enzyme ◽

Phenotypic Traits ◽

Kinase Gene ◽

Enzyme Preparations ◽

Mitogen Activated Protein

Mitogen-activated protein (MAP) kinases represent a group of serine/threonine protein kinases playing a central role in signal transduction processes in eukaryotic cells. Using a strategy based on the complementation of the thermosensitive autolytic phenotype of slt2 null mutants, we have isolated a Candida albicans homolog of Saccharomyces cerevisiae MAP kinase gene SLT2 (MPK1), which is involved in the recently outlined PKC1-controlled signalling pathway. The isolated gene, named MKC1 (MAP kinase from C. albicans), coded for a putative protein, Mkc1p, of 58,320 Da that displayed all the characteristic domains of MAP kinases and was 55% identical to S. cerevisiae Slt2p (Mpk1p). The MKC1 gene was deleted in a diploid Candida strain, and heterozygous and homozygous strains, in both Ura+ and Ura- backgrounds, were obtained to facilitate the analysis of the function of the gene. Deletion of the two alleles of the MKC1 gene gave rise to viable cells that grew at 28 and 37 degrees C but, nevertheless, displayed a variety of phenotypic traits under more stringent conditions. These included a low growth yield and a loss of viability in cultures grown at 42 degrees C, a high sensitivity to thermal shocks at 55 degrees C, an enhanced susceptibility to caffeine that was osmotically remediable, and the formation of a weak cell wall with a very low resistance to complex lytic enzyme preparations. The analysis of the functions downstream of the MKC1 gene should contribute to understanding of the connection of growth and morphogenesis in pathogenic fungi.

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Activation of mitogen-activated protein kinase and p70S6 kinase is not correlated with cerebellar granule cell survival

Biochemical Journal ◽

10.1042/bj3240365 ◽

1997 ◽

Vol 324 (2) ◽

pp. 365-369 ◽

Cited By ~ 42

Author(s):

Frank J. GUNN-MOORE ◽

Alan G. WILLIAMS ◽

Nicholas J. TOMS ◽

Jeremy M. TAVARÉ

Keyword(s):

Map Kinase ◽

Granule Cells ◽

Cerebellar Granule Cells ◽

Mitogen Activated Protein Kinase ◽

Kinase Activation ◽

Cerebellar Granule ◽

P70s6 Kinase ◽

Mitogen Activated Protein ◽

Sustained Activation

We have investigated the role of mitogen-activated protein (MAP) kinase in the survival of cerebellar granule cells in primary culture. Brain-derived neurotrophic factor (BDNF) and insulin, but not epidermal growth factor (EGF), promoted the survival of P6 cerebellar granule neurons. BDNF promoted a sustained activation of MAP kinase, whereas that induced by EGF was only transient. Insulin promoted a small but transient activation of MAP kinase that was completely blocked by PD98059, an inhibitor of MAP kinase kinase activation. PD98059 had no effect on the insulin- or BDNF-induced survival of cerebellar granule cells. We also investigated the role of p70S6 kinase in survival. The activation of p70S6 kinase by EGF was transient, whereas BDNF and insulin promoted a sustained activation of p70S6 kinase. Rapamycin, which blocked p70S6 kinase activation, had no effect on the BDNF- or insulin-induced survival of cerebellar granule cells. We conclude that sustained activation of MAP kinase is not correlated with the survival response of cerebellar granule cells; indeed insulin-mediated survival is independent of MAP kinase. Survival of cerebellar granule cells is also independent of the activation of p70S6 kinase.

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Role of a Mitogen-Activated Protein Kinase Cascade in Ion Flux-Mediated Turgor Regulation in Fungi

Eukaryotic Cell ◽

10.1128/ec.5.3.480-487.2006 ◽

2006 ◽

Vol 5 (3) ◽

pp. 480-487 ◽

Cited By ~ 34

Author(s):

Roger R. Lew ◽

Natalia N. Levina ◽

Lana Shabala ◽

Marinela I. Anderca ◽

Sergey N. Shabala

Keyword(s):

Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Wild Type ◽

Turgor Regulation ◽

Map Kinase Cascade ◽

Protein Map ◽

Mitogen Activated Protein ◽

Kinase Cascade ◽

Protein Kinase Cascade

ABSTRACT Fungi normally maintain a high internal hydrostatic pressure (turgor) of about 500 kPa. In response to hyperosmotic shock, there are immediate electrical changes: a transient depolarization (1 to 2 min) followed by a sustained hyperpolarization (5 to 10 min) prior to turgor recovery (10 to 60 min). Using ion-selective vibrating probes, we established that the transient depolarization is due to Ca2+ influx and the sustained hyperpolarization is due to H+ efflux by activation of the plasma membrane H+-ATPase. Protein synthesis is not required for H+-ATPase activation. Net K+ and Cl− uptake occurs at the same time as turgor recovery. The magnitude of the ion uptake is more than sufficient to account for the osmotic gradients required for turgor to return to its original level. Two osmotic mutants, os-1 and os-2, homologs of a two-component histidine kinase sensor and the yeast high osmotic glycerol mitogen-activated protein (MAP) kinase, respectively, have lower turgor than the wild type and do not exhibit the sustained hyperpolarization after hyperosmotic treatment. The os-1 mutant does not exhibit all of the wild-type turgor-adaptive ion fluxes (Cl− uptake increases, but net K+ flux barely changes and net H+ efflux declines) (os-2 was not examined). Both os mutants are able to regulate turgor but at a lower level than the wild type. Our results demonstrate that a MAP kinase cascade regulates ion transport, activation of the H+-ATPase, and net K+ and Cl− uptake during turgor regulation. Other pathways regulating turgor must also exist.

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Tumour necrosis factor-α-induced phosphorylation and activation of cytosolic phospholipase A2 are abrogated by an inhibitor of the p38 mitogen-activated protein kinase cascade in human neutrophils

Biochemical Journal ◽

10.1042/bj3190017 ◽

1996 ◽

Vol 319 (1) ◽

pp. 17-20 ◽

Cited By ~ 91

Author(s):

Waltraut H WATERMAN ◽

Thaddeus F. P. MOLSKI ◽

Chi-Kuang HUANG ◽

Jerry L. ADAMS ◽

Ramadan I. SHA'AFI

Keyword(s):

Map Kinase ◽

P38 Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Human Neutrophils ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Kinase Cascade ◽

Factor Α ◽

Sb 203580

The role of the newly identified p38 mitogen-activated protein kinase (MAP kinase) in terminally differentiated cells, such as human neutrophils, is totally unknown. In order to examine the possible role of this MAP kinase in the phosphorylation and activation of cytoplasmic phospholipase A2 (cPLA2), we tested the effect of the recently synthesized inhibitor of p38 MAP kinase, SB 203580, on the phosphorylation and activation of both p38 MAP kinase and cPLA2. We found that while tumour necrosis factor-α (TNF-α)-stimulated tyrosine phosphorylation of p38 MAP kinase is affected only slightly by SB 203580, its stimulated kinase activity is greatly reduced in human neutrophils in suspension treated with this inhibitor. Furthermore, the TNF-α-stimulated phosphorylation and activation of cPLA2 are completely abolished in cells treated with SB 203580. Based on these data, it is reasonable to conclude that an SB 203580-sensitive kinase, or kinases and/or phosphatases, are involved in the phosphorylation and activation of cPLA2 in intact human neutrophils in suspension stimulated by TNF-α. The possible role of the p38 MAP kinase cascade in the phosphorylation and activation of cPLA2 is discussed.

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Hog1 Controls Lipids Homeostasis Upon Osmotic Stress in Candida albicans

Journal of Fungi ◽

10.3390/jof6040355 ◽

2020 ◽

Vol 6 (4) ◽

pp. 355

Author(s):

Carmen Herrero-de-Dios ◽

Elvira Román ◽

Jesús Pla ◽

Rebeca Alonso-Monge

Keyword(s):

Candida Albicans ◽

Osmotic Stress ◽

Lipid Droplets ◽

Opportunistic Pathogen ◽

Mitogen Activated Protein Kinase ◽

Cell Permeability ◽

Lipid Homeostasis ◽

Mitogen Activated Protein ◽

Osmotic Challenge

As opportunistic pathogen, Candida albicans adapts to different environmental conditions and its corresponding stress. The Hog1 MAPK (Mitogen Activated Protein Kinase) was identified as the main MAPK involved in the response to osmotic stress. It was later shown that this MAPK is also involved in the response to a variety of stresses and therefore, its role in virulence, survival to phagocytes and establishment as commensal in the mouse gastrointestinal tract was reported. In this work, the role of Hog1 in osmotic stress is further analyzed, showing that this MAPK is involved in lipid homeostasis. The hog1 mutant accumulates lipid droplets when exposed to osmotic stress, leading to an increase in cell permeability and delaying the endocytic trafficking routes. Cek1, a MAPK also implicated in the response to osmotic challenge, did not play a role in lipid homeostasis indicating that Hog1 is the main MAP kinase in this response. The alteration on lipid metabolism observed in hog1 mutants is proposed to contribute to the sensitivity to osmotic stress.

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