From Lipid Homeostasis to Differentiation: Old and New Functions of the Zinc Cluster Proteins Ecm22, Upc2, Sut1 and Sut2

Abstract

Zinc cluster proteins are a large family of transcriptional regulators with a wide range of biological functions. The zinc cluster proteins Ecm22, Upc2, Sut1 and Sut2 have initially been identified as regulators of sterol import in the budding yeast Saccharomyces cerevisiae. These proteins also control adaptations to anaerobic growth, sterol biosynthesis as well as filamentation and mating. Orthologs of these zinc cluster proteins have been identified in several species of Candida. Upc2 plays a critical role in antifungal resistance in these important human fungal pathogens. Upc2 is therefore an interesting potential target for novel antifungals. In this review we discuss the functions, mode of actions and regulation of Ecm22, Upc2, Sut1 and Sut2 in budding yeast and Candida.

A Novel Sterol-Signaling Pathway Governs Azole Antifungal Drug Resistance and Hypoxic Gene Repression in Saccharomyces cerevisiae

“…In Saccharomyces cerevisiae and other yeast species, ergosterol biosynthesis is an oxygen-dependent pathway (Parks and Casey 1995;Kwast et al 1998;Rosenfeld and Beauvoit 2003;Espenshade and Hughes 2007;Ishtar Snoek and Yde Steensma 2007). Under hypoxic or anaerobic conditions, ergosterol production is blocked, leading to its depletion (Rosenfeld and Beauvoit 2003;Joshua and Höfken 2017). Yeast respond to ergosterol depletion by signaling structural changes in the cell wall to facilitate uptake of exogenous ergosterol (Abramova et al 2001;Alimardani et al 2004;Ishtar Snoek and Yde Steensma 2007;Zavrel et al 2013).…”

“…To maintain ergosterol homeostasis, ergosterol (ERG) genes, which encode enzymes needed for ergosterol biosynthesis, are tightly controlled by transcription factors (Kwast et al 2002;Davies et al 2005;Davies and Rine 2006;Hickman and Winston 2007;Ishtar Snoek and Yde Steensma 2007;Joshua and Höfken 2017). Three transcription factors that are known to regulate ERG genes include Hap1, Ecm22, and Upc2 (Fytlovich et al 1993;Vik and Rine 2001;Becerra et al 2002;Ter Linde and Steensma 2002;Tamura et al 2004;Davies et al 2005;Davies and Rine 2006).…”

“…Upc2 and Ecm22 are paralogs and activate genes in response to sterol levels. During sterol depletion using statin or antifungal azole drugs, ERG genes are induced by Upc2 and Ecm22 (Vik and Rine 2001;Wilcox et al 2002;Davies et al 2005;Davies and Rine 2006;Joshua and Höfken 2017).…”

Ergosterol reduction impairs mitochondrial DNA maintenance in S. cerevisiae

“…In S. cerevisiae, the ERG27 is essential since its absence causes a complete block of ergosterol synthesis, but the ∆erg27 strain associated with upc2-1 mutation is able to grow in a medium supplemented with the minimal requirement of 0.02mg/ml of ergosterol. Upc2p is a general regulator of the expression of ERG genes[52][53][54] and the upc2-1 mutation also increases the potency of the activation domain[55]. Since we cannot exclude an involvement of upc2-1 mutation in the ∆erg27 phenotypes, as a control, we also measured the percentage of petites in a ∆erg27 strain transformed with the ERG27 wild type gene (strain called ∆erg27+pST10(ERG27)).…”

Overexpression of Ecm22 improves ergosterol biosynthesis inSaccharomyces cerevisiae

“…a, the invasive growth in YS1 and YS2 was clearly improved. Considering the expression levels of ERG genes are upregulated in an Ecm22/Upc2‐dependent manner during filamentation (Woods and Höfken ; Joshua and Höfken ), Ecm22 and Upc2 can positively regulate invasive growth in haploid YS58 through improving ergosterol biosynthesis (Fig. ).…”