Calcineurin-Crz1 Signaling in Lower Eukaryotes

Abstract

Calcium ions are ubiquitous intracellular messengers. An increase in the cytosolic Ca 2؉ concentration activates many proteins, including calmodulin and the Ca 2؉ /calmodulin-dependent protein phosphatase calcineurin. The phosphatase is conserved from yeast to humans (except in plants), and many target proteins of calcineurin have been identified. The most prominent and bestinvestigated targets, however, are the transcription factors NFAT (nuclear factor of activated T cells) in mammals and Crz1 (calcineurin-responsive zinc finger 1) in yeast. In recent years, many orthologues of Crz1 have been identified and characterized in various species of fungi, amoebae, and other lower eukaryotes. It has been shown that the functions of calcineurin-Crz1 signaling, ranging from ion homeostasis through cell wall biogenesis to the building of filamentous structures, are conserved in the different organisms. Furthermore, frequency-modulated gene expression through Crz1 has been discovered as a striking new mechanism by which cells can coordinate their response to a signal. In this review, I focus on the latest findings concerning calcineurin-Crz1 signaling in fungi, amoebae and other lower eukaryotes. I discuss the potential of Crz1 and its orthologues as putative drug targets, and I also discuss possible parallels with calcineurin-NFAT signaling in mammals.

The putative flavin carrier family FlcA-C is important forAspergillus fumigatusvirulence

“…[1][2][3][4][5] The calcineurin phosphatase and the transcription factor Crz1p1/CrzA are essential for fungal calcium signaling. 1,2 In Saccharomyces cerevisiae, several environmental stresses, for instance osmotic, extreme pH, high temperature, ER stress and prolonged incubation with mating pheromone a-factor, are regulated by calcineurin. 5,6 Calcineurin also connects many stress response signaling pathways.…”

“…[8][9][10][11][12] Calcineurin activates the transcription factor Crz1 (Calcineurin Responsive Zinc Finger 1) transcription factor by dephosphorylating it when there in an increase cytosolic calcium and permitting its translocation to the nuclei. 1,13 Crz1 has a C 2 H 2 zinc finger motif responsible for the binding to a CDRE (calcineurindependent response element) sequence in the promoter regions of the Crz1-regulated genes. 1,14 Fungal infections are becoming very important considering that presently there is a larger number of people dying from fungal infections than malaria and tuberculosis, what is due to the increase of the number of patients with immunosuppression.…”

“…1,13 Crz1 has a C 2 H 2 zinc finger motif responsible for the binding to a CDRE (calcineurindependent response element) sequence in the promoter regions of the Crz1-regulated genes. 1,14 Fungal infections are becoming very important considering that presently there is a larger number of people dying from fungal infections than malaria and tuberculosis, what is due to the increase of the number of patients with immunosuppression. 15 The signaling by calcium is very important for fungal virulence and drug resistance.…”

“…15 The signaling by calcium is very important for fungal virulence and drug resistance. 1,2 Calcineurin has been demonstrated to be required for virulence in human fungal pathogens, such as Cryptococcus spp, Candida spp, Paracoccidioides brasiliensis, and Aspergillus fumigatus; [16][17][18][19][20][21][22][23] and fungal plant pathogens, such as Sclerotinia scleotiorum, Botrytis cinerea, Magnaporthe oryza, and Ustilago spp. [24][25][26][27][28] In all these fungal pathogens, calcineurin is important for growth, morphology, state transitions, cation homeostasis, stress responses, and cell membrane and cell wall integrity pathways.…”

“…[24][25][26][27][28] In all these fungal pathogens, calcineurin is important for growth, morphology, state transitions, cation homeostasis, stress responses, and cell membrane and cell wall integrity pathways. 1,2,[29][30][31][32][33] Aspergillus fumigatus is an opportunistic fungal pathogen and the most important species causing pulmonary fungal infections. 15,[34][35][36][37][38] Although A. fumigatus is able to cause many clinical forms, the most important is the invasive pulmonary aspergillosis (IPA), that has mortality rates as high as 80% in immunosuppressed patients.…”