Involvement of the mitogen activated protein kinase Hog1p in the response of Candida albicans to iron availability

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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Mitogen-activated protein kinase-defective Candida albicans is avirulent in a novel model of localized murine candidiasis

FEMS Microbiology Letters ◽

10.1111/j.1574-6968.1998.tb13194.x ◽

1998 ◽

Vol 166 (1) ◽

pp. 135-139 ◽

Cited By ~ 29

Author(s):

Faisal A Guhad ◽

Henrik E Jensen ◽

B Aalbaek ◽

Csilla Csank ◽

Othman Mohamed ◽

...

Keyword(s):

Candida Albicans ◽

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Novel Model

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Msb2 Signaling Mucin Controls Activation of Cek1 Mitogen-Activated Protein Kinase in Candida albicans

Eukaryotic Cell ◽

10.1128/ec.00081-09 ◽

2009 ◽

Vol 8 (8) ◽

pp. 1235-1249 ◽

Cited By ~ 79

Author(s):

Elvira Román ◽

Fabien Cottier ◽

Joachim F. Ernst ◽

Jesús Pla

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Protein Kinase ◽

Osmotic Shock ◽

Mitogen Activated Protein Kinase ◽

Hog Pathway ◽

High Osmolarity ◽

Cell Wall Biogenesis ◽

Solid Media ◽

Mitogen Activated Protein

ABSTRACT We have characterized the role that the Msb2 protein plays in the fungal pathogen Candida albicans by the use of mutants defective in the putative upstream components of the HOG pathway. Msb2, in cooperation with Sho1, controls the activation of the Cek1 mitogen-activated protein kinase under conditions that damage the cell wall, thus defining Msb2 as a signaling element of this pathway in the fungus. msb2 mutants display altered sensitivity to Congo red, caspofungin, zymolyase, or tunicamycin, indicating that this protein is involved in cell wall biogenesis. Msb2 (as well as Sho1 and Hst7) is involved in the transmission of the signal toward Cek1 mediated by the Cdc42 GTPase, as revealed by the use of activated alleles (Cdc42G12V) of this protein. msb2 mutants have a stronger defective invasion phenotype than sho1 mutants when tested on certain solid media that use mannitol or sucrose as a carbon source or under hypoxia. Interestingly, Msb2 contributes to growth under conditions of high osmolarity when both branches of the HOG pathway are altered, as triple ssk1 msb2 sho1 mutants (but not any single or double mutant) are osmosensitive. However, this phenomenon is independent of the presence of Hog1, as Hog1 phosphorylation, Hog1 translocation to the nucleus, and glycerol accumulation are not affected in this mutant following an osmotic shock. These results reveal essential functions in morphogenesis, invasion, cell wall biogenesis, and growth under conditions of high osmolarity for Msb2 in C. albicans and suggest the divergence and specialization of this signaling pathway in filamentous fungi.

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Mitogen activated protein kinase-1 and cell division control protein-42 are putative targets for the binding of novel natural lead molecules: a therapeutic intervention against Candida albicans

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2019.1682053 ◽

2019 ◽

Vol 38 (15) ◽

pp. 4584-4599 ◽

Cited By ~ 1

Author(s):

Dharshini Gopal ◽

Aditi G Muddebihalkar ◽

Sinosh Skariyachan ◽

Akshay Uttarkar C ◽

Prinith Kaveramma ◽

...

Keyword(s):

Candida Albicans ◽

Cell Division ◽

Protein Kinase ◽

Therapeutic Intervention ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Control Protein ◽

Cell Division Control

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Histatin 5 Initiates Osmotic Stress Response in Candida albicans via Activation of the Hog1 Mitogen-Activated Protein Kinase Pathway

Eukaryotic Cell ◽

10.1128/ec.00039-07 ◽

2007 ◽

Vol 6 (10) ◽

pp. 1876-1888 ◽

Cited By ~ 69

Author(s):

Slavena Vylkova ◽

Woong Sik Jang ◽

Wansheng Li ◽

Namrata Nayyar ◽

Mira Edgerton

Keyword(s):

Oxidative Stress ◽

Candida Albicans ◽

Stress Response ◽

Protein Kinase ◽

Osmotic Stress ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Hog Pathway ◽

Histatin 5 ◽

Mitogen Activated Protein

ABSTRACT Histatin 5 (Hst 5) is a salivary cationic peptide that has toxicity for Candida albicans by inducing rapid cellular ion imbalance and cell volume loss. Microarray analyses of peptide-treated cells were used to evaluate global gene responses elicited by Hst 5. The major transcriptional response of C. albicans to Hst 5 was expression of genes involved in adaptation to osmotic stress, including production of glycerol (RHR2, SKO1, and PDC11) and the general stress response (CTA1 and HSP70). The oxidative-stress genes AHP1, TRX1, and GPX1 were mildly induced by Hst 5. Cell defense against Hst 5 was dependent on the Hog1 mitogen-activated protein kinase (MAPK) pathway, since C. albicans hog1/hog1 mutants were significantly hypersensitive to Hst 5 but not to Mkc1 MAPK or Cek1 MAPK mutants. Activation of the high-osmolarity glycerol (HOG) pathway was demonstrated by phosphorylation of Hog1 MAPK as well as by glycerol production following Hst 5 treatment in a dose-dependent manner. C. albicans cells prestressed with sorbitol were less sensitive to subsequent Hst 5 treatment; however, cells treated concurrently with osmotic stress and Hst 5 were hypersensitive to Hst 5. In contrast, cells subjected to oxidative stress had no difference in sensitivity to Hst 5. These results suggest a common underlying cellular response to osmotic stress and Hst 5. The HOG stress response pathway likely represents a significant and effective challenge to physiological levels of Hst 5 and other toxic peptides in fungal cells.

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Inhibition of Monocytic Interleukin-12 Production by Candida albicans via Selective Activation of ERK Mitogen-Activated Protein Kinase

Infection and Immunity ◽

10.1128/iai.72.5.2513-2520.2004 ◽

2004 ◽

Vol 72 (5) ◽

pp. 2513-2520 ◽

Cited By ~ 29

Author(s):

Ningfeng Tang ◽

Liming Liu ◽

Kefei Kang ◽

Pranab K. Mukherjee ◽

Masakazu Takahara ◽

...

Keyword(s):

Candida Albicans ◽

Protein Kinase ◽

Inhibitory Activity ◽

Biochemical Analysis ◽

Specific Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Interleukin 12 ◽

Mitogen Activated Protein ◽

Ifn Γ ◽

Stimulating Factor

ABSTRACT Our previous data demonstrated that live Candida albicans inhibits interleukin-12 (IL-12) production by human monocytes. Here we explored whether C. albicans inhibits IL-12 via a released factor and whether the inhibition is mediated via mitogen-activated protein kinase (MAPK) regulation. Supernatant fluids were obtained from cultured C. albicans (SC5314) as well as cultured Saccharomyces cerevisiae after 20 h of incubation. At 2 h postincubation of monocytes with heat-killed C. albicans (HKCA) (2:1) to stimulate IL-12, concentrated fungal supernatant fluids were added and incubated for an additional 20 h. The present data show that, unlike supernatant fluids obtained from S. cerevisiae, the C. albicans supernatant fluids significantly suppressed IL-12 production induced by HKCA. This suggested that the inhibition is Candida specific. A preliminary biochemical analysis revealed that this secretory IL-12 inhibitory factor is glycoprotein in nature. The inhibitory activity had no effect on the phagocytosis of yeasts. Supernatant fluids from C. albicans markedly induced the phosphorylation of ERK44/42 MAPK, but not p38 and SAPK, 1 min after they were added to monocytes. To test if the induction of ERK44/42 MAPK was central to the IL-12 inhibition, we used gamma interferon (IFN-γ) (1 ng/ml) plus lipopolysaccharide (LPS) (100 ng/ml) to stimulate IL-12 production by monocytes. The inhibition of ERK MAPK by the specific inhibitor PD 98059 significantly reduced phospho-ERK44/42 MAPK levels induced by C. albicans supernatant fluids in the IFN-γ-plus-LPS-driven monocytes. Concomitantly, PD 98059 reversed the IL-12 inhibitory activity of the C. albicans supernatant (P < 0.01). These data indicate that C. albicans can inhibit IL-12 production by secreting an ERK44/42 MAPK-stimulating factor and thus can attenuate effective immune responses.

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