Academic journal article Genetics

Conserved and Diverged Functions of the Calcineurin-Activated Prz1 Transcription Factor in Fission Yeast

Academic journal article Genetics

Conserved and Diverged Functions of the Calcineurin-Activated Prz1 Transcription Factor in Fission Yeast

Article excerpt

CALCINEURIN is a highly conserved phosphatase central to Ca2+ signaling. In metazoans, calcineurin regulates a wide array of Ca2+-dependent processes including T-cell activation (Clipstone and Crabtree 1992), cardiac hypertrophy (Molkentin et al. 1998), neutrophil motility (Hendey et al. 1992), apoptosis (Wang et al. 1999), angiogenesis (Graef et al. 2001), and memory development (Mansuy et al. 1998). One of the primary effectors of calcineurin is the NFAT family of transcription factors, which translocates into the nucleus to regulate target genes when dephosphorylated (reviewed in Macian 2005). In fungi, the activity of the Crz1 C2H2 zinc-finger transcription factor is modulated by calcineurin in a similar way (reviewed in Thewes 2014). Crz1 orthologs have been identified in various fungal species and their function appears conserved in cell-wall-related processes and resistance to external stressors (Thewes 2014).

The Saccharomyces cerevisiae Crz1 is localized in the cytosol under optimal growth conditions, but is activated and rapidly translocated into the nucleus through dephosphorylation by calcineurin in response to exogenous Ca2+ (Stathopoulos-Gerontides et al. 1999). In addition to exogenous Ca2+, Crz1 is activated by numerous external stresses including high salt, prolonged exposure to a-factor, alkaline pH, antifungal compounds, blue light, nutrient deprivation, heavy metals, and ethanol (Matheos et al. 1997; Stathopoulos and Cyert 1997; Edlind et al. 2002; Serrano et al. 2002; Zakrzewska et al. 2005; Zhang and Rao 2007; Ruiz et al. 2008; Araki et al. 2009; Ferreira et al. 2012; Bodvard et al. 2013). Transcriptome profiling of CRZ1 was initially performed with Ca2+ or Na+ treatment that identified 163 target genes (Yoshimoto et al. 2002), and this list has been expanded subsequently with similar profiling under alkaline stress, nutrient deprivation, and transcription factor overexpression (Viladevall et al. 2004; Chua et al. 2006; Ruiz et al. 2008). The Crz1 target genes are known to function in ion homeostasis, small-molecule transport, cell-wall maintenance, lipid and sterol metabolism, and vesicle transport. Many of these target genes contain the calcineurin-dependent response element (CDRE) motif [59-GNGGC(G/T)CA-39]intheir promoter (Yoshimoto et al. 2002). Crz1 binds this motif, which was originally discovered in the promoter of FKS2, and is sufficient to drive the transcriptional activation of a reporter gene (Stathopoulos and Cyert 1997; Yoshimoto et al. 2002).

In Schizosaccharomyces pombe, the Ppb1 calcineurin catalytic subunit dephosphorylates the transcription factor Prz1 in response to elevated Ca2+ levels (Hirayama et al. 2003). Similar to other Crz1 orthologs, dephosphorylation of Prz1 causes nuclear translocation and transcriptional regulation of its target genes through binding of a CDRE-like motif (59-AGCCTC-39)(Denget al. 2006) or a Ca2+-dependent response element (59-CAACT-39)(Hamasaki-Katagiriand Ames 2010). Loss of prz1+ produces a normal phenotype under optimal growth conditions, but results in hypersensitivity to Ca2+ and reduced mating efficiency (Hirayama et al. 2003; Sun et al. 2013). In contrast, the calcineurin Dppb1 strain exhibits a more severe phenotype with additional defects in cytokinesis, cell polarity, and chloride hypersensitivity (Yoshida et al. 1994; Hirayama et al. 2003). These defects are not suppressed by prz1+overexpression, indicating that Prz1 is not the sole target of calcineurin (Hirayama et al. 2003). In addition to Ca2+, activation of Prz1 occurs upon exposure to NaCl, DTT and tunicamycin (ER stressors), micafungin (a b-glucanase inhibitor), and heat shock, when assayed by a CDRE-regulated reporter, nuclear translocation, or prz1+ messenger RNA levels (Hirayama et al. 2003; Deng et al. 2006). In addition, prz1+ overexpression activates the CDRE-regulated reporter, thus indicating positive autoregulation (Koike et al. 2012). The response to diverse external stimuli indicates that Prz1 must regulate genes involved in multiple cellular processes as observed in other fungal orthologs. …

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