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1.
Int J Mol Sci ; 23(24)2022 Dec 11.
Article in English | MEDLINE | ID: mdl-36555348

ABSTRACT

Understanding which intracellular signaling pathways are activated by manganese stress is crucial to decipher how metal overload compromise cellular integrity. Here, we unveil a role for oxidative and cell wall stress signaling in the response to manganese stress in yeast. We find that the oxidative stress transcription factor Yap1 protects cells against manganese toxicity. Conversely, extracellular manganese addition causes a rapid decay in Yap1 protein levels. In addition, manganese stress activates the MAPKs Hog1 and Slt2 (Mpk1) and leads to an up-regulation of the Slt2 downstream transcription factor target Rlm1. Importantly, Yap1 and Slt2 are both required to protect cells from oxidative stress in mutants impaired in manganese detoxification. Under such circumstances, Slt2 activation is enhanced upon Yap1 depletion suggesting an interplay between different stress signaling nodes to optimize cellular stress responses and manganese tolerance.


Subject(s)
Manganese , Mitogen-Activated Protein Kinases , Saccharomyces cerevisiae Proteins , Transcription Factors , Manganese/toxicity , Manganese/metabolism , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
2.
Int J Mol Sci ; 23(19)2022 Sep 20.
Article in English | MEDLINE | ID: mdl-36232332

ABSTRACT

The cell wall integrity pathway (CWI) is a MAPK-mediated signaling route essential for yeast cell response to cell wall damage, regulating distinct aspects of fungal physiology. We have recently proven that the incorporation of a genetic circuit that operates as a signal amplifier into this pathway allows for the identification of novel elements involved in CWI signaling. Here, we show that the strong growth inhibition triggered by pathway hyperactivation in cells carrying the "Integrity Pathway Activation Circuit" (IPAC) also allows the easy identification of new stimuli. By using the IPAC, we have found various chemical agents that activate the CWI pathway, including the aminoglycoside neomycin. Cells lacking key components of this pathway are sensitive to this antibiotic, due to the disruption of signaling upon neomycin stimulation. Neomycin reduces both phosphatidylinositol-4,5-bisphosphate (PIP2) availability at the plasma membrane and myriocin-induced TORC2-dependent Ypk1 phosphorylation, suggesting a strong interference with plasma membrane homeostasis, specifically with PIP2. The neomycin-induced transcriptional profile involves not only genes related to stress and cell wall biogenesis, but also to amino acid metabolism, reflecting the action of this antibiotic on the yeast ribosome.


Subject(s)
Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae , Amino Acids/metabolism , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Cell Membrane/metabolism , Cell Wall/metabolism , Inositol Phosphates/metabolism , Mechanistic Target of Rapamycin Complex 2/metabolism , Mitogen-Activated Protein Kinases/metabolism , Neomycin/pharmacology , Phosphatidylinositols/metabolism , Phosphorylation , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism
3.
FEBS J ; 287(22): 4881-4901, 2020 11.
Article in English | MEDLINE | ID: mdl-32150787

ABSTRACT

The cell wall integrity (CWI) pathway mediates the response of Saccharomyces cerevisiae to cell wall alterations. Stress at the cell surface is detected by mechanosensors, which transduce the signal to a protein kinase cascade that involves Pkc1, Bck1, Mkk1/Mkk2, the mitogen-activated protein kinase (MAPK) Slt2 and the transcription factor Rlm1. We incorporated a positive feedback loop into this pathway by placing a hyperactive MKK1 allele under the control of the Rlm1-regulated MLP1 promoter. This circuit operates as a signal amplifier and leads to a highly increased Slt2 activation under stimulating conditions. Triggering the CWI pathway in cells engineered with this circuit, which we have named the Integrity Pathway Activation Circuit (IPAC), results in strong growth inhibition. Exploitation of this hypersensitive phenotype allowed the identification of novel proteins that contribute in signalling to Rlm1 in response to cell surface stressing agents such as Congo red, zymolyase and SDS. Among these proteins, the MAPK kinase kinase Ssk2 of the osmoregulatory high-osmolarity glycerol (HOG) pathway, but not its paralogue Ssk22, proved to be necessary for the SDS-induced IPAC-mediated growth inhibition. We found the existence of an Ssk1-independent Ssk2-Pbs2-Hog1-CWI pathway signalling axis that contributes to Slt2 activation in response to cell surface stress. We also demonstrated that the MAP kinase kinases Mkk1 and Pbs2 and the MAPKs Slt2 and Hog1 of the HOG and CWI pathways interact physically, forming a complex. Our results show how a simple synthetic circuit can be used as a powerful tool for a better understanding of signalling pathways.


Subject(s)
Cell Wall/metabolism , Feedback, Physiological , MAP Kinase Kinase Kinases/metabolism , MAP Kinase Signaling System , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/metabolism , Cell Wall/genetics , Gene Expression Regulation, Fungal , MAP Kinase Kinase Kinases/genetics , Microscopy, Fluorescence , Osmoregulation/genetics , Phosphorylation , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics , Stress, Mechanical
4.
Int Microbiol ; 23(1): 107-119, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31342212

ABSTRACT

The Saccharomyces cerevisiae cell wall integrity (CWI) pathway took this name when its role in the cell response to cell wall aggressions was clearly established. The receptors involved in sensing the damage, the relevant components operating in signaling to the MAPK Slt2, the transcription factors activated by this MAPK, as well as some key regulatory mechanisms have been identified and characterized along almost 30 years. However, other stimuli that do not alter specifically the yeast cell wall, including protein unfolding, low or high pH, or plasma membrane, oxidative and genotoxic stresses, have been also found to trigger the activation of this pathway. In this review, we compile almost forty non-cell wall-specific compounds or conditions, such as tunicamycin, hypo-osmotic shock, diamide, hydroxyurea, arsenate, and rapamycin, which induce these stresses. Relevant aspects of the CWI-mediated signaling in the response to these non-conventional pathway activators are discussed. The data presented here highlight the central and key position of the CWI pathway in the safeguard of yeast cells to a wide variety of external aggressions.


Subject(s)
Cell Wall/metabolism , Signal Transduction , Yeasts/physiology , Cell Membrane/metabolism , Cytoskeleton/metabolism , DNA Damage , Endoplasmic Reticulum Stress , Mitogen-Activated Protein Kinases/metabolism , Stress, Physiological
5.
Am J Trop Med Hyg ; 91(2): 267-72, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24980494

ABSTRACT

This study was designed to examine the height-for-age z-scores (HAZ), and the prevalence of intestinal inflammation, gastrointestinal infections with parasites, and enteroaggregative Escherichia coli (EAEC) in rural Panamanian children. Stool microscopy and polymerase chain reaction (PCR) testing for EAEC detected Giardia lamblia (32%, 32 of 100) and EAEC (13%, 11 of 87) in the study participants, respectively. Anthropometric analyses showed that those children who were > 12 months of age had lower HAZ scores (mean of -1.449) than the reference population. As a group, the children in the study 1 to 5 years of age did not show recovery from the previously mentioned decline in terms of their HAZ. The HAZ means of the children infected with G. lamblia, EAEC, and Ascaris lumbricoides were -1.49, -1.67, and -2.11, respectively. Furthermore, the study participants with A. lumbricoides and EAEC infections in the presence of lactoferrin showed another decrease of 0.19 and 0.13, respectively, in their HAZ means.


Subject(s)
Ascariasis/epidemiology , Diarrhea/epidemiology , Escherichia coli Infections/epidemiology , Giardiasis/epidemiology , Intestines , Animals , Ascariasis/parasitology , Ascaris lumbricoides/isolation & purification , Body Height , Child , Child, Preschool , Diarrhea/microbiology , Escherichia coli/isolation & purification , Escherichia coli Infections/microbiology , Feces/microbiology , Feces/parasitology , Female , Giardia lamblia/isolation & purification , Giardiasis/parasitology , Humans , Infant , Intestines/microbiology , Intestines/parasitology , Male , Panama/epidemiology , Polymerase Chain Reaction , Prevalence , Rural Population
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