Hybrid histidine kinases in pathogenic fungi

Defosse, Tatiana A.; Sharma, Anupam; Mondal, Alok K.; Bernonville, Thomas Dugé de; Latgé, Jean‐Paul; Calderone, Richard; Giglioli-Guivarc’h, Nathalie; Courdavault, Vincent; Clastre, Marc; Papon, Nicolas

doi:10.1111/mmi.12911

Cited by 76 publications

(110 citation statements)

References 77 publications

(96 reference statements)

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“…[39][40][41] One of the better known MAPK pathways that utilizes 2-component proteins is the Hog1p pathway. Environmental signals that trigger the HOG1 MAPK include high osmotic pressure and ROS.…”

Section: The Mitochondrial Srr1p Response Regulatormentioning

confidence: 99%

Exploiting mitochondria as targets for the development of new antifungals

Calderone

2016

Virulence

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Section: The Mitochondrial Srr1p Response Regulatormentioning

confidence: 99%

Exploiting mitochondria as targets for the development of new antifungals

Calderone

2016

Virulence

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“…Blastomyces dermatitidis, the agent of blastomycosis, harbors the group III HHK Drk1 (dimorphism-regulating kinase) (6,28). In the present study, we heterologously expressed Drk1 in S. cerevisiae to study the mode of action of fludioxonil.…”

mentioning

confidence: 99%

“…Most pathogenic fungi harbor group III HHKs (6), which should sensitize them to phenylpyrrole drugs such as fludioxonil. Blastomyces dermatitidis, the agent of blastomycosis, harbors the group III HHK Drk1 (dimorphism-regulating kinase) (6,28).…”

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Fludioxonil Induces Drk1, a Fungal Group III Hybrid Histidine Kinase, To Dephosphorylate Its Downstream Target, Ypd1

Lawry

Tebbets

Kean

et al. 2017

Antimicrob Agents Chemother

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Novel antifungal drugs and targets are urgently needed. Group III hybrid histidine kinases (HHKs) represent an appealing new therapeutic drug target because they are widely expressed in fungi but absent from humans. We investigated the mode of action of the widely utilized, effective fungicide fludioxonil. The drug acts in an HHK-dependent manner by constitutive activation of the HOG (highosmolarity glycerol) pathway, but its mechanism of action is poorly understood. Here, we report a new mode of drug action that entails conversion of the HHK from a kinase into a phosphatase. We expressed Drk1 (dimorphism-regulating kinase), which is an intracellular group III HHK from the fungal pathogen Blastomyces dermatitidis, in Saccharomyces cerevisiae. Drk1 engendered drug sensitivity in B. dermatitidis and conferred sensitivity upon S. cerevisiae. In response to fludioxonil, Drk1 behaved as a phosphatase rather than as a kinase, leading to dephosphorylation of its downstream target, Ypd1, constitutive activation of the HOG pathway, and yeast cell death. Aspartic acid residue 1140 in the Drk1 receiver domain was required for in vivo phosphatase activity on Ypd1, and Hog1 was required for drug effect, indicating fidelity in HHK-dependent drug action. In in vitro assays with purified protein, intact Drk1 demonstrated intrinsic kinase activity, and the Drk1 receiver domain exhibited intrinsic phosphatase activity. However, fludioxonil failed to induce intact Drk1 to dephosphorylate Ypd1. We conclude that fludioxonil treatment in vivo likely acts on an upstream target that triggers HHK to become a phosphatase, which dephosphorylates its downstream target, Ypd1.

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“…After glutamine synthesis, arginine synthesis takes place with help of the enzyme arginosuccinate synthetase and arginine is the final product utilized by plants in case of AM fungi Barman et al, (2016). Although some other interesting roles were reported for a few series of fungal histidinekinase, but they currently appear species-specific including melanin production, adaptation to hypoxia, regulation of secondary metabolism, and biofilm formation Defosse et al, (2015). Bashar and Rai (1994) observed that A. flavus and A. niger amended in soil suppressed the growth of FOC and exhibited strong fungistatic activity against germination of conidia of test pathogen.…”

Section: Effect Of Aspergillu Sniger Isolates On Physiological Paramementioning

confidence: 99%