Involvement of the Aspergillus nidulans protein kinase C with farnesol tolerance is related to the unfolded protein response

Abstract

SummaryPreviously, we demonstrated that the Aspergillus nidulans calC2 mutation in protein kinase C pkcA was able to confer tolerance to farnesol (FOH), an isoprenoid that has been shown to inhibit proliferation and induce apoptosis. Here, we investigate in more detail the role played by A. nidulans pkcA in FOH tolerance. We demonstrate that pkcA overexpression during FOH exposure causes increased cell death. FOH is also able to activate several markers of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Our results suggest an intense cross-talk between PkcA and the UPR during FOH-induced cell death. Furthermore, the overexpression of pkcA increases both mRNA accumulation and metacaspases activity, and there is a genetic interaction between PkcA and the caspase-like protein CasA. Mutant analyses imply that MAP kinases are involved in the signal transduction in response to the effects caused by FOH.

Metacaspases

“…Nuclear translocation of metacaspases during cell disassembly in the Norway spruce embryo-suspensors 6 and in the dying epimastigotes of Trypanosoma cruzi 34 indirectly supports this scenario. By contrast, the antagonistic control of cell death by two type I metacaspases, such as the one shown for the Arabidopsis HR 26 and A. nidulans ER stress 25 suggests a possible role in the decision phase.…”

“…24 Redundancy may not always be the case, as two Aspergillus nidulans metacaspases antagonistically control ER stressinduced cell death, one metacaspase (CasA) acting as positive regulator and another as a negative one (CasB). 25 Similarly, a recent study also documented the antagonistic functions of two Arabidopsis type I metacaspases, AtMC1 and AtMC2, in mediating hypersensitive response (HR)-associated cell death (Table 2). 26 Compared with genomes of protozoa and fungi with a single or a few type I metacaspase genes and no type II metacaspase genes, genomes of higher plants encode larger metacaspase families including both type I and type II members; for example, there are nine and twelve metacaspase genes in A. thaliana and Populus trichocarpa, respectively ( Figure 1; http://merops.sanger.ac.uk/).…”

“…27 A similar requirement for a metacaspase has been reported in the fission yeast, albeit for a more limited number of cell death conditions, including lipotoxic stress 18 and inositol starvation 19 ( Table 2). Further in the fungi kingdom it has been established that both PaMca1 and PaMca2 are required for senescence-associated cell death in P. anserina, 23 a single Candida albicans metacaspase, CaMCA1, mediates oxidative stress-induced cell death in this pathogenic yeast, 28 whereas one of the two metacaspases, CasA, promotes ER stressassociated cell death in A. nidulans 25 (Table 2). A pro-cell death role of metacaspases has now been extended to protozoa and plants.…”

Transcriptome changes initiated by carbon starvation in Aspergillus nidulans

“…Many of them, including pdiA and mns1B as well as AN2738 and AN1117 (encoding putative COPII-coated vesicle membrane proteins), were related to endoplasmic reticulum functions. The upregulation of pdiA (Colabardini et al, 2010) and hacA (Table 2), an orthologue of the S. cerevisiae hac1 bZIP-type transcription factor (Mori et al, 1996;Saloheimo et al, 2003), suggested the activation of the unfolded-protein stress response under carbon starvation. The induction of these genes can be explained by the increased need for formation of extracellular proteins (see above) in carbonstarved cultures.…”

The Aspergillus nidulans nucA EndoG Homologue Is Not Involved in Cell Death

“…We have been using Aspergillus nidulans and the isoprenoid farnesol (FOH), which inhibits proliferation and induces apoptosis, as a model system and cell death stimulus, respectively, aiming to understand by which means filamentous fungi are driven toward cell death (3,5,20,23). In mammalian cells, at least two major apoptotic pathways have been depicted: (i) the intrinsic pathway, which needs the involvement of the mitochondria, and (ii) the extrinsic pathway, where mitochondria are bypassed and caspases are activated (for a review, see reference 6).…”