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

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.
Molecular Microbiology (Impact Factor: 4.42). 12/2010; 78(5):1259-79. DOI: 10.1111/j.1365-2958.2010.07403.x
Source: PubMed


Previously, 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.

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    • "In the filamentous fungus Aspergillus nidulans, PkcA was shown to be fundamental to the cell wall integrity (CWI) pathway, is essential for viability, and has been shown to be involved in penicillin production, polarized growth, morphogenesis, septum formation and the apoptosis [5]–[9]. Crosstalk between Pkc and the unfolded protein response (UPR) or other MAP (mitogen-activated protein) kinase cascades has been observed [10], [11]. "
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    • "Overexpression of pkcA in ΔcasA cells restored the sensitivity to farnesol-induced apoptosis. These observations led the authors to speculate that in A. nidulans metacaspases may function antagonistically with casA promoting death while casB has a protective role during ER stress (Colabardini et al., 2010). "
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    • "Two proteins have been identified in this response; the Gα subunit FadA of a heterotrimeric G protein, where hyperactivation leads to a strong increase in farnesol sensitivity [38], and the kinase PkcA. Mutation of PkcA increases resistance to farnesol while overexpression results in a higher rate of cell death in response to the QSM [41]. Finally, farnesol has also been described to induce apoptosis of cancerous cells in vivo (see review [42]), as well as increasing antibiotic sensitivity of Staphylococcus aureus [43]. "
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