Farnesol misplaces tip‐localized Rho proteins and inhibits cell wall integrity signalling in Aspergillus fumigatus

Abstract

SummaryFarnesol is known for inducing apoptosis in some fungi and mammalian cells. To evaluate its potential role as an antifungal agent, we studied its impact on the human pathogen Aspergillus fumigatus. We found that growth of A. fumigatus wild type is inhibited, but two cell wall mutants, Dmnt1 and DglfA, are much more susceptible to farnesol. This susceptibility is partially rescued by osmotic stabilization, suggesting that farnesol is a cell wall perturbing agent. However, farnesol does not activate but inhibit the cell wall integrity (CWI) pathway. Remarkably, mutants lacking AfMkk2 or AfMpkA, two kinases essential for CWI signalling, are also highly susceptible to farnesol, suggesting that its mode of action goes beyond inhibition of CWI signalling. Farnesyl derivatives are known for interfering with the function of prenylated proteins. We analysed the subcellular localization of two prenylated Rho family GTPases, AfRho1 and AfRho3, which are implicated in controlling CWI and the cytoskeleton. We found that under normal growth conditions AfRho1 and AfRho3 predominantly localize to the hyphal tip. After farnesol treatment this localization is rapidly lost, which is accompanied by swelling of the hyphal tips. Parallel displacement of tropomyosin from the tips suggests a concomitant disorganization of the apical actin cytoskeleton.

Volatile sesquiterpenes from fungi: what are they good for?

“…Additionally, C. effect was shown to be also due to volatile transmission of the sesquiterpene alcohol (Semighini et al 2006). Similar alterations by farnesol in growth and morphology are described in the Ascomycota species Fusarium graminearum, Aspergillus niger and Aspergillus fumigatus (Lorek et al 2008;Semighini et al 2008;Dichtl et al 2010). Dichtl et al further suggest that farnesol is interfering in the CWI pathway (cell wall integrity) of which many components are conserved within the kingdom fungi and therefore display an advantage in competition for farnesol-producing fungal species.…”

“…Subphylum, Class Volatile sesquiterpenes References Ascocoryne comprises saprobic fungi growing on dead wood Ascocoryne sarcoides Pezizomycotina, Leotiomycetes X Griffin et al 2010 Aspergillus grows saprotrophic in soil and on decaying organic matter; comprises also human pathogens Aspergillus fumigatus * Pezizomycotina, Eurotiomycetes 1, 2, 3, 67 Sunesson et al 1995Nozoe et al 1976Dichtl et al 2010 Aspergillus versicolor * Pezizomycotina, Eurotiomycetes…”

The SrkA Kinase Is Part of the SakA Mitogen-Activated Protein Kinase Interactome and Regulates Stress Responses and Development in Aspergillus nidulans

“…It is interesting that the abundance of 15 proteins that interact with SakA or SrkA after H 2 O 2 exposure is altered by farnesol or menadione treatment (see Table S2 in the supplemental material), as these compounds induce the generation of ROS (84,85) and provoke apoptosis and cell cycle arrest in yeasts and filamentous fungi (84,86,87). In fact, SakA mediates the induction of the dplA gene by farnesol, which encodes a putative dehydrin involved in conidium resistance to H 2 O 2 (54).…”

Role of the Guanine Nucleotide Exchange Factor Rom2 in Cell Wall Integrity Maintenance of Aspergillus fumigatus

“…1) and of other molds. We and others have shown that the Aspergillus CWI MAP kinase module consisting of the MAP kinase kinase kinase Bck1, the MAP kinase kinase Mkk2, and the MAP kinase MpkA is highly conserved from yeasts to molds (6)(7)(8)(9). Several studies suggest the involvement of protein kinase C (PkcA), but direct proof that places PkcA in line with the MAP kinase module in Aspergillus spp.…”