The Molecular Mechanism of Fludioxonil Action Is Different to Osmotic Stress Sensing

Abstract

The group III two-component hybrid histidine kinase MoHik1p in the filamentous fungus Magnaporthe oryzae is known to be a sensor for external osmotic stress and essential for the fungicidal activity of the phenylpyrrole fludioxonil. The mode of action of fludioxonil has not yet been completely clarified but rather assumed to hyperactivate the high osmolarity glycerol (HOG) signaling pathway. To date, not much is known about the detailed molecular mechanism of how osmotic stress is detected or fungicidal activity is initiated within the HOG pathway. The molecular mechanism of signaling was studied using a mutant strain in which the HisKA signaling domain was modified by an amino acid change of histidine H736 to alanine A736. We found that MoHik1pH736A is as resistant to fludioxonil but not as sensitive to osmotic stress as the null mutant ∆Mohik1. H736 is required for fludioxonil action but is not essential for sensing sorbitol stress. Consequently, this report provides evidence of the difference in the molecular mechanism of fludioxonil action and the perception of osmotic stress. This is an excellent basis to understand the successful phenylpyrrole-fungicides’ mode of action better and will give new ideas to decipher cellular signaling mechanisms.

Molecular Mechanisms of Fungal Signaling

“…The HHKs are the primary sensor proteins of the signaling cascade, with variable sensory domains at the N-terminus (e.g. HAMP or HAMP-like linker domains (poly-HAMP)), an HK domain with an autophosphorylation site [147] [148] [149] and a Histidine similar ATPase catalytic domain (HATPase domain). The C-terminal response regulator domain (REC) within the HHK contains the Asp phosphoacceptor residue [149].…”

“…The phosphotransfer, for example, in the HKK Nik1p in C. albicans occurs from aa H510 within the HisKA domain to aa D924 within the REC domain [153] [154]. The His-Asp phosphorylation pattern within a HKK in M. oryzae is located at aa position H736 in the HisKA domain [147] [133] [149], and the phosphoryl group is transferred to the phosphoacceptor at position D1153 in the REC domain [155]. The aa position His69 is predicted to play an important role in the phosphoryl transfer activity of the HPt domain within the phosphotransfer protein Ypd1p in C. albicans [145] [156].…”

“…This means that no homologues have been found in plants or mammals to date. These HHKs are known to be involved in the mode of action of the commercial fungicide fludioxonil [147] [163] [164]. Consequently, research on MSP leads to new opportunities to develop novel antifungal compounds without causing significant toxicity to other organisms in the environment [165] [159] [145] [135].…”

BEM2, a RHO GTPase Activating Protein That Regulates Morphogenesis in S. cerevisiae, Is a Downstream Effector of Fungicidal Action of Fludioxonil

“…Fludioxonil belongs to the phenylpyrrole group of fungicides with a broad antifungal spectrum. It is used to control a variety of plant-pathogenic fungi [ 1 , 2 , 3 , 4 ]. Previous studies have revealed that fludioxonil acts as a fungicide through the inhibition of Nik1 orthologs or Group III hybrid histidine kinase (HHK3), which leads to the improper activation of the p38/HOG MAPK pathway in fungal pathogens [ 5 , 6 , 7 , 8 , 9 ].…”

Special Issue “Signal Transductions in Fungi”

“…Four articles investigated the effect of osmotic stress on sensing. The relationship between external osmotic stress sensing and the fungicidal activity of phenylpyrrole fludioxonil was the subject of a study by Bersching and Jacob [ 4 ]. Essential to both processes seems to be a group III two-component hybrid histidine kinase.…”