Transcriptional Profiling Identifies Two Members of the ATP-binding Cassette Transporter Superfamily Required for Sterol Uptake in Yeast

Wilcox, Lisa J.; Balderes, Dina; Wharton, Brook; Tinkelenberg, Arthur H.; Rao, Govinda; Sturley, Stephen L.

doi:10.1074/jbc.m204707200

Cited by 233 publications

(308 citation statements)

References 36 publications

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“…Previous experiments have shown that ABC transporters are able to translocate membrane phospholipids and sterols and function in controlling or modulating membrane lipid homeostasis, regulation of membrane permeability and phospholipid bilayer distribution (Wilcox et al, 2002;Li and Prinz, 2004). In Saccharomyces cerevisiae cells producing high levels of carotenoids, the membrane buffering capacity to accumulate the produced carotenoids may not be sufficient.…”

Section: Discussionmentioning

confidence: 99%

Heterologous carotenoid production in Saccharomyces cerevisiae induces the pleiotropic drug resistance stress response

Verwaal

Jiang

Wang

et al. 2010

Yeast

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To obtain insight into the genome-wide transcriptional response of heterologous carotenoid production in Saccharomyces cerevisiae, the transcriptome of two different S. cerevisiae strains overexpressing carotenogenic genes from the yeast Xanthophyllomyces dendrorhous grown in carbon-limited chemostat cultures was analysed. The strains exhibited different absolute carotenoid levels as well as different intermediate profiles. These discrepancies were further sustained by the difference of the transcriptional response exhibited by the two strains. Transcriptome analysis of the strain producing high carotenoid levels resulted in specific induction of genes involved in pleiotropic drug resistance (PDR). These genes encode ABC-type and major facilitator transporters which are reported to be involved in secretion of toxic compounds out of cells. β-Carotene was found to be secreted when sunflower oil was added to the medium of S. cerevisiae cells producing high levels of carotenoids, which was not observed when added to X. dendrorhous cells. Deletion of pdr10, one of the induced ABC transporters, decreased the transformation efficiency of a plasmid containing carotenogenic genes. The few transformants that were obtained had decreased growth rates and lower carotenoid production levels compared to a pdr5 deletion and a reference strain transformed with the same genes. Our results suggest that production of high amounts of carotenoids in S. cerevisiae leads to membrane stress, in which Pdr10 might play an important role, and a cellular response to secrete carotenoids out of the cell.

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Section: Discussionmentioning

confidence: 99%

Heterologous carotenoid production in Saccharomyces cerevisiae induces the pleiotropic drug resistance stress response

Verwaal

Jiang

Wang

et al. 2010

Yeast

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“…Finally, two additional plasma membrane PDRtransporters, Aus1p and Pdr11p, may be involved in sterol uptake when endogenous sterol biosynthesis is impaired, as for example during anaerobic growth [19]. AUS1 is also upregulated in response to azole treatment [20], implying that it could mediate drug efflux.…”

Section: Plasma Membrane Abc Transporters -The First Defense Linementioning

confidence: 99%

“…Based on genome-wide transcriptional profiling of a Upc2-1 gain-of-function mutant strain that exhibits aerobic sterol influx, PDR11 and AUS1 were identified as major determinants required for uptake of free sterols under conditions of impaired ergosterol biosynthesis [19].…”

Section: Regulation Of Abc Gene Expression In S Cerevisiaementioning

confidence: 99%

Yeast ABC transporters – A tale of sex, stress, drugs and aging

2005

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Yeast ATP-binding cassette (ABC) proteins are implicated in many biological phenomena, often acting at crossroads of vital cellular processes. Their functions encompass peptide pheromone secretion, regulation of mitochondrial function, vacuolar detoxification, as well as pleiotropic drug resistance and stress adaptation. Because yeast harbors several homologues of mammalian ABC proteins with medical importance, understanding their molecular mechanisms, substrate interaction and three-dimensional structure of yeast ABC proteins might help identifying new approaches aimed at combating drug resistance or other ABC-mediated diseases. This review provides a comprehensive discussion on the functions of the ABC protein family in the yeast Saccharomyces cerevisiae.

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“…These proteins then mediate sterol influx. Presumably, other proteins contribute to this process as well (Wilcox et al, 2002;Alimardani et al, 2004).Here, we characterize the link between proteins regulating sterol uptake and the PAKs Ste20, Cla4 and Skm1. Our data suggest a model (Figure 1), according to which PAKs shuttle into the nucleus, where they interact with Sut1 and possibly other transcriptional regulators and down-regulate the expression of AUS1, DAN1, and PDR11.…”

mentioning

confidence: 99%

“…Sterol uptake is controlled by the transcriptional regulators Sut1, Upc2, and Ecm22, which are members of the Zn(II)2Cys6 family of DNA-binding proteins (Schjerling and Holmberg, 1996). Under anaerobic conditions, Upc2 and Sut1 up-regulate the expression of the ATP-binding cassette transporter AUS1 and PDR11, and the putative cell wall mannoprotein DAN1 (Figure 1) Wilcox et al, 2002;Alimardani et al, 2004). These proteins then mediate sterol influx.…”

mentioning

confidence: 99%

The Cdc42 Effectors Ste20, Cla4, and Skm1 Down-Regulate the Expression of Genes Involved in Sterol Uptake by a Mitogen-activated Protein Kinase-independent Pathway

Lin

Unden

Jacquier

et al. 2009

MBoC

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In Saccharomyces cerevisiae, the Rho-type GTPase Cdc42 regulates polarized growth through its effectors, including the p21-activated kinases (PAKs) Ste20, Cla4, and Skm1. Previously, we demonstrated that Ste20 interacts with several proteins involved in sterol synthesis that are crucial for cell polarization. Under anaerobic conditions, sterols cannot be synthesized and need to be imported into cells. Here, we show that Ste20, Cla4, and Skm1 form a complex with Sut1, a transcriptional regulator that promotes sterol uptake. All three PAKs can translocate into the nucleus and down-regulate the expression of genes involved in sterol uptake, including the Sut1 targets AUS1 and DAN1 by a novel mechanism. Consistently, deletion of either STE20, CLA4, or SKM1 results in an increased sterol influx and PAK overexpression inhibits sterol uptake. For Ste20, we demonstrate that the down-regulation of gene expression requires nuclear localization and kinase activity of Ste20. Furthermore, the Ste20-mediated control of expression of sterol uptake genes depends on SUT1 but is independent of a mitogen-activated protein kinase signaling cascade. Together, these observations suggest that PAKs translocate into the nucleus, where they modulate expression of sterol uptake genes via Sut1, thereby controlling sterol homeostasis. INTRODUCTIONThe small Rho GTPase Cdc42 plays a central role in the regulation of cellular polarity in eukaryotic cells (EtienneManneville, 2004;Jaffe and Hall, 2005). In the budding yeast Saccharomyces cerevisiae, Cdc42 regulates different types of polarized growth during various phases of its life cycle, including budding during vegetative growth, mating between haploid cells of opposite mating types, and filamentous growth upon nutrient limitation (Park and Bi, 2007). Cdc42 promotes polarized growth through multiple pathways, including polarization of the actin cytoskeleton and directed vesicle trafficking. Among the Cdc42 effectors that trigger these pathways are Ste20, Cla4 and Skm1, members of the p21-activated kinase (PAK) family of serine/threonine protein kinases (Hofmann et al., 2004;Park and Bi, 2007).Cdc42 recruits Ste20 and Cla4 from the cytoplasm and activates them at the plasma membrane at sites of polarized growth. Therefore, Ste20 and Cla4 are enriched at tips of buds and mating projections (Peter et al., 1996;Leberer et al., 1997;Holly and Blumer, 1999). The recruitment of Ste20 and Cla4 to these sites is governed by protein-protein as well as protein-lipid interactions. PAKs carry a conserved Cdc42/ Rac-interactive binding (CRIB) domain that mediates binding to Cdc42 and regulates their activity (Cvrckova et al., 1995;Peter et al., 1996;Leberer et al., 1997;Lamson et al., 2002;Ash et al., 2003). Ste20 and Cla4 also bind to Bem1, a scaffold protein that brings Cdc42, its activator Cdc24 and either Ste20 or Cla4, into proximity (Leeuw et al., 1998;Gulli et al., 2000;Bose et al., 2001;Yamaguchi et al., 2007). In addition, phosphoinositide-binding domains promote the association with membrane lip...

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Transcriptional Profiling Identifies Two Members of the ATP-binding Cassette Transporter Superfamily Required for Sterol Uptake in Yeast

Cited by 233 publications

References 36 publications

Heterologous carotenoid production in Saccharomyces cerevisiae induces the pleiotropic drug resistance stress response

Heterologous carotenoid production in Saccharomyces cerevisiae induces the pleiotropic drug resistance stress response

Yeast ABC transporters – A tale of sex, stress, drugs and aging

The Cdc42 Effectors Ste20, Cla4, and Skm1 Down-Regulate the Expression of Genes Involved in Sterol Uptake by a Mitogen-activated Protein Kinase-independent Pathway

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