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Intracellular mechanism by which arsenite activates the yeast stress MAPK Hog1.

ABSTRACT: Stress-activated MAPKs (SAPKs) respond to a wide variety of stressors. In most cases, the pathways through which specific stress signals are transmitted to the SAPKs are not known. In this study, we delineate the intracellular signaling pathway by which the trivalent toxic metalloid arsenite [As(III)] activates the yeast SAPK Hog1. We demonstrate that, to activate Hog1, As(III) must enter the cell through the glycerol channel Fps1 and must be metabolized to methyl arsenite [MAs(III)] by the dimeric methyltransferase Mtq2:Trm112. We found that Mtq2:Trm1 displays SAM-dependent methyltransferase activity toward both As(III) and MAs(III). Additionally, we present genetic and biochemical evidence that MAs(III), but not As(III), is a potent inhibitor of the protein tyrosine phosphatases (Ptp2 and Ptp3) that normally maintain Hog1 in an inactive state. Inhibition of Ptp2 and Ptp3 by MAs(III) results in elevated Hog1 phosphorylation without activation of the protein kinases that act upstream of the SAPK and raises the possibility that other Hog1-activating stressors act intracellularly at different points along the canonical Hog1 activation pathway. Finally, we show that arsenate [As(V)], a pentavalent form of arsenic, also activates Hog1, but through a pathway that is distinct from that of As(III) and involves activation of the Hog1 MEK Pbs2.

SUBMITTER: Lee J

PROVIDER: S-EPMC6085820 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Intracellular mechanism by which arsenite activates the yeast stress MAPK Hog1.

Lee Jongmin J Levin David E DE

Molecular biology of the cell 20180530 15

Stress-activated MAPKs (SAPKs) respond to a wide variety of stressors. In most cases, the pathways through which specific stress signals are transmitted to the SAPKs are not known. In this study, we delineate the intracellular signaling pathway by which the trivalent toxic metalloid arsenite [As(III)] activates the yeast SAPK Hog1. We demonstrate that, to activate Hog1, As(III) must enter the cell through the glycerol channel Fps1 and must be metabolized to methyl arsenite [MAs(III)] by the dime ...[more]

PMID: 29846136

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Project description:Candida albicans is the most common fungal pathogen and relies on the Hog1-MAPK pathway to resist osmotic stress posed by the environment or during host invasions. Here, we investigated the role of SPT20 in response to osmotic stress. Testing a C. albicans spt20Δ/Δ mutant, we found it was sensitive to osmotic stress. Using sequence alignment, we identified the conserved functional domains between CaSpt20 and ScSpt20. Reconstitution of the Spt20 function in a spt20Δ/CaSPT20 complemented strain found CaSPT20 can suppress the high sensitivity to hyperosmotic stressors, a cell wall stress agent, and antifungal drugs in the Saccharomyces cerevisiae spt20Δ/Δ mutant background. We measured the cellular glycerol accumulation and found it was significantly lower in the C. albicans spt20Δ/Δ mutant strain, compared to the wild type strain SC5314 (P < 0.001). This result was also supported by quantitative reverse transcription-PCR, which showed the expression levels of gene contributing to glycerol accumulation were reduced in Caspt20Δ/Δ compared to wild type (GPD2 and TGL1, P < 0.001), while ADH7 and AGP2, whose expression can lead to glycerol decrease, were induced when cells were exposed to high osmolarity (ADH7, P < 0.001; AGP2, P = 0.002). In addition, we tested the transcription levels of Hog1-dependent osmotic stress response genes, and found that they were significantly upregulated in wild type cells encountering hyperosmolarity, while the expression of HGT10, SKO1, CAT1, and SLP3 were not induced when SPT20 was deleted. Although the transcript of ORF19.3661 and ORF19.4370 in Caspt20Δ/Δ was induced in the presence of 1 M NaCl, the levels were less than what was observed in the wild type (ORF19.3661, P = 0.007; ORF19.4370, P = 0.011). Moreover, the deletion of CaSPT20 in C. albicans reduced phosphorylation levels of Hog1. These findings suggested that SPT20 is conserved between yeast and C. albicans and plays an important role in adapting to osmotic stress through regulating Hog1-MAPK pathway.

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Intracellular mechanism by which arsenite activates the yeast stress MAPK Hog1.

Publications

Intracellular mechanism by which arsenite activates the yeast stress MAPK Hog1.

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