Differential Role of HAMP-like Linkers in Regulating the Functionality of the Group III Histidine Kinase DhNik1p

Kaur, Harsimran; Singh, Samiksha; Rathore, Yogendra Singh; Sharma, Anupam; Furukawa, Kentaro; Hohmann, Stefan; Ashish, .; Mondal, Alok K.

doi:10.1074/jbc.m114.554303

Cited by 16 publications

(13 citation statements)

References 44 publications

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“…Treatment causes constitutive Hog1 phosphorylation (32)(33)(34) and cell death, whereas deletion of pathway components engenders drug resistance (29,31,35). The drug's action also requires the N-terminal HAMP domain repeats that are a signature feature of group III HHKs (27,36). Moreover, fungal crop pests that acquire resistance to fludioxonil or dicarboximides, another class of antifungals that also require group III HHKs, reveal mutations in these HAMP domains (9,37,38).…”

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confidence: 99%

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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confidence: 99%

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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“…This pattern is quite distinct from the high osmolarity-induced activation of Hog1p where the activation of Hog1p is transient and returns to the basal level mostly within 1 h (8). Earlier studies showed that DhNik1p, an HHK3 from the yeast Debaryomyces hansenii, regulated the HOG/p38 MAPK pathway through Ypd1p-Ssk1p phosphorelay in S. cerevisiae in a manner similar to that of Sln1p (13,20,22). ClNik1p could also be acting through Ypd1p to regulate Hog1p.…”

Section: Fludioxonil Exerts Its Toxic Effect On S Cerevisiae Expressmentioning

confidence: 92%

“…Earlier studies indicated that the p38/HOG MAPK pathway plays a pivotal role in the fungicidal action of fludioxonil (14,20,22). Besides this pathway, involvement of the cell wall integrity pathway and calcineurin-mediated signaling have also been implicated (11).…”

Section: Role Of Corvet Complex In Fungicidal Action Of Fludioxonilmentioning

confidence: 99%

“…Analysis of the HHK3 mutants in several species indicates that it functions as a sensor upstream of the HOG/p38 MAPK pathway. HHK3 was found to complement Sln1p in S. cerevisiae and regulate the HOG/ p38 MAPK pathway in a similar manner (13,20,22). Fungicidal action of fludioxonil involves inhibition of HHK3, resulting in the constitutive activation of the Hog1p MAPK in fungi.…”

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confidence: 96%

“…However, the heterologous expression of HHK3 confers fludioxonil sensitivity to this host, which further confirms the role of HHK3 in the toxic effect of fludioxonil on fungal cells (19 -21). HHK3 is one of the most conserved and widely characterized among the fungal HHKs (14,22). Analysis of the HHK3 mutants in several species indicates that it functions as a sensor upstream of the HOG/p38 MAPK pathway.…”

mentioning

confidence: 99%

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Overexpression of the CORVET complex alleviates the fungicidal effects of fludioxonil on the yeast Saccharomyces cerevisiae expressing hybrid histidine kinase 3

Randhawa

Kundu

Sharma

et al. 2019

Journal of Biological Chemistry

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Candida: A Model Fungus to Study Differentiation, Pathogenesis, and Bioprospecting

Pathan

Deshpande²

2021

Progress in Mycology

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Differential Role of HAMP-like Linkers in Regulating the Functionality of the Group III Histidine Kinase DhNik1p

Cited by 16 publications

References 44 publications

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

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

Overexpression of the CORVET complex alleviates the fungicidal effects of fludioxonil on the yeast Saccharomyces cerevisiae expressing hybrid histidine kinase 3

Candida: A Model Fungus to Study Differentiation, Pathogenesis, and Bioprospecting

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