Saccharomyces cerevisiae PIP2 Mediating Oleic Acid Induction and Peroxisome Proliferation Is Regulated by Adr1p and Pip2p-Oaf1p

Rottensteiner, Hanspeter; Wabnegger, Leila; Erdmann, Ralf; Hamilton, Barbara; Ruis, Helmut; Hartig, Andreas; Gurvitz, Aner

doi:10.1074/jbc.m304097200

Cited by 26 publications

(24 citation statements)

References 52 publications

(55 reference statements)

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“…These sequence elements have been shown to be bound coordinately by Pip2p/Oaf1p and Adr1p, respectively, to activate transcription under oleate growth conditions (22,23). Second, Adr1p has been implicated in the binding and activation of the PIP2 promoter (38). These findings support a model whereby Snf1p posttranslationally activates Adr1p, which induces the transcription of PIP2 and coordinates with the Oaf1p/Pip2p complex to directly activate the transcription of a subset of genes (60,61).…”

Section: Discussionsupporting

confidence: 72%

Mxr1p, a Key Regulator of the Methanol Utilization Pathway and Peroxisomal Genes in Pichia pastoris

Lin-Cereghino

Godfrey

Cruz

et al. 2006

Molecular and Cellular Biology

141

192

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Growth of the yeast Pichia pastoris on methanol induces the expression of genes whose products are required for its metabolism. Three of the methanol pathway enzymes are located in an organelle called the peroxisome. As a result, both methanol pathway enzymes and proteins involved in peroxisome biogenesis (PEX proteins) are induced in response to this substrate. The most highly regulated of these genes is AOX1, which encodes alcohol oxidase, the first enzyme of the methanol pathway, and a peroxisomal enzyme. To elucidate the molecular mechanisms responsible for methanol regulation, we identify genes required for the expression of AOX1. Mutations in one gene, named MXR1 (methanol expression regulator 1), result in strains that are unable to (i) grow on the peroxisomal substrates methanol and oleic acid, (ii) induce the transcription of AOX1 and other methanol pathway and PEX genes, and (iii) form normal-appearing peroxisomes in response to methanol. MXR1 encodes a large protein with a zinc finger DNA-binding domain near its N terminus that has similarity to Saccharomyces cerevisiae Adr1p. In addition, Mxr1p is localized to the nucleus in cells grown on methanol or other gluconeogenic substrates. Finally, Mxr1p specifically binds to sequences upstream of AOX1. We conclude that Mxr1p is a transcription factor that is necessary for the activation of many genes in response to methanol. We propose that MXR1 is the P. pastoris homologue of S. cerevisiae ADR1 but that it has gained new functions and lost others through evolution as a result of changes in the spectrum of genes that it controls.The ability to utilize methanol as a carbon and energy source is limited in eukaryotes to a few yeast species (1,34,57). The metabolic pathway is nearly identical in each species and begins with the oxidation of methanol to formaldehyde, which is catalyzed by the peroxisomal matrix enzyme alcohol oxidase (Aox). A by-product of this reaction is hydrogen peroxide, which is subsequently degraded to water and oxygen by a second peroxisomal enzyme catalase (Cat). The formaldehyde generated by Aox follows one of two paths. A portion leaves the peroxisome and is further oxidized by two cytoplasmic enzymes, formaldehyde dehydrogenase (Fld) and formate dehydrogenase (Fdh), to generate energy for the cell. The remaining formaldehyde is condensed with xylulose-5-phosphate by a third peroxisomal enzyme, dihydroxyacetone synthase (Dhas), to generate two three-carbon molecules that leave the peroxisome and enter a cyclic pathway that regenerates xylulose-5-phosphate and produces one net molecule of glyceraldehyde-3-phosphate for every three turns of this cycle (1, 57).Because three of the methanol pathway enzymes (Aox, Cat, and Dhas) are peroxisomal, the function of this organelle is also essential for methanol growth (21,26,33). This observation has made Pichia pastoris a major model system for the elucidation of peroxisome biogenesis and function (2,40,49). One advantage of P. pastoris for peroxisome studies is that in addition to methanol uti...

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Section: Discussionsupporting

confidence: 72%

Mxr1p, a Key Regulator of the Methanol Utilization Pathway and Peroxisomal Genes in Pichia pastoris

Lin-Cereghino

Godfrey

Cruz

et al. 2006

Molecular and Cellular Biology

141

192

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“…In the case of the plant pathogen M. grisea, this included members of the cutinase gene family, and the motif was also found upstream of cutinase genes as well as a predicted lipase in A. nidulans. S. cerevisiae lacks farA and farB orthologs, and fatty acid induction is dependent on the Oaf1/Pip2 heterodimer (29,34,35,58). Consistent with this, the CCTCGG motif was not overrepresented in the 5Ј region of relevant genes from S. cerevisiae (Table 2).…”

supporting

confidence: 69%

“…Acetyl-CoA produced in the peroxisome is converted to acetyl-carnitine for export to the cytosol and the mitochondrion (18,39,63,79,80). The related transcriptional activators Oaf1 and Pip2 containing DNA binding domains of the Zn 2 -Cys 6 binuclear class together with Adr1, a C 2 H 2 zinc finger protein, are responsible for this induction via the cis-acting elements (ORE) and UAS1, respectively (4,25,34,35,48,57,58). The genes for metabolism of the resulting acetyl-CoA by the glyoxalate bypass and gluconeogenesis is controlled by the Zn 2 -Cys 6 binuclear proteins Cat8 and Sip4 acting at carbon source-responsive elements (CSREs) in the 5Ј region of the relevant genes (26,27,54,55,56,81).…”

mentioning

confidence: 99%

Regulatory Genes Controlling Fatty Acid Catabolism and Peroxisomal Functions in the Filamentous Fungus Aspergillus nidulans

et al. 2006

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The catabolism of fatty acids is important in the lifestyle of many fungi, including plant and animal pathogens. This has been investigated in Aspergillus nidulans, which can grow on acetate and fatty acids as sources of carbon, resulting in the production of acetyl coenzyme A (CoA). Acetyl-CoA is metabolized via the glyoxalate bypass, located in peroxisomes, enabling gluconeogenesis. Acetate induction of enzymes specific for acetate utilization as well as glyoxalate bypass enzymes is via the Zn 2 -Cys 6 binuclear cluster activator FacB. However, enzymes of the glyoxalate bypass as well as fatty acid beta-oxidation and peroxisomal proteins are also inducible by fatty acids. We have isolated mutants that cannot grow on fatty acids. Two of the corresponding genes, farA and farB, encode two highly conserved families of related Zn 2 -Cys 6 binuclear proteins present in filamentous ascomycetes, including plant pathogens. A single ortholog is found in the yeasts Candida albicans, Debaryomyces hansenii, and Yarrowia lipolytica, but not in the Ashbya, Kluyveromyces, Saccharomyces lineage. Northern blot analysis has shown that deletion of the farA gene eliminates induction of a number of genes by both short-and long-chain fatty acids, while deletion of the farB gene eliminates short-chain induction. An identical core 6-bp in vitro binding site for each protein has been identified in genes encoding glyoxalate bypass, beta-oxidation, and peroxisomal functions. This sequence is overrepresented in the 5 region of genes predicted to be fatty acid induced in other filamentous ascomycetes, C. albicans, D. hansenii, and Y. lipolytica, but not in the corresponding genes in Saccharomyces cerevisiae.It has become increasingly clear that the breakdown of fatty acids is important in the metabolism, development, and pathogenicity of many fungi. Catabolism occurs via the beta-oxidation pathway, in which fatty acids are activated to the corresponding acyl coenzyme A (CoA) and then oxidation by a series of enzyme steps releases acetyl-CoA and an acyl-CoA shortened by two carbons, which can undergo additional cycles of beta-oxidation. In mammals, beta-oxidation of long-chain fatty acids occurs in peroxisomes, while medium-and shortchain fatty acids undergo beta-oxidation in the mitochondria (reviewed in references 16 and 84). In contrast, in Saccharomyces cerevisiae fatty acids are metabolized entirely in peroxisomes (reviewed in reference 29). In fungi, where fatty acids can serve as sole sources of carbon and energy, the acetyl-CoA must be converted to C 4 compounds via the glyoxalate bypass, comprising the enzymes isocitrate lyase and malate synthase, allowing gluconeogenesis (40, 64). Isocitrate lyase and malate synthase are usually, but not always, located in peroxisomes. It has been found that mutations affecting isocitrate lyase, malate synthase, and peroxisomal functions can affect the pathogenicity of both plant and animal pathogens (33,37,45,46,66). Furthermore it has been found that genes encoding enzymes for fatty acid catabol...

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“…Although most of the peroxins that are involved in peroxisome biogenesis are not induced by fatty acids, peroxins such as Pex11p/Pmp27p and Pex25p, which are involved in peroxisome proliferation, are regulated by the OAF1-PIP2 pathway (42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54). Interestingly, the promoter of PIP2 contains ORE, and its expression is induced by fatty acids, whereas the expression of Oaf1p is constitutive (54).…”

Section: Peroxisome Proliferationmentioning

confidence: 99%

ER stress response, peroxisome proliferation, mitochondrial unfolded protein response and Golgi stress response

Yoshida

2009

IUBMB Life

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The endoplasmic reticulum (ER) response has been thought a cytoprotective mechanism to cope with accumulation of unfolded proteins in the ER. Recent progress has made a quantum leap revealing that ER stress response can be regarded as an autoregulatory system adjusting the ER capacity to cellular demand. This Copernican change raised a novel fundamental question in cell biology: how do cells regulate the capacity of each organelle in accordance with cellular needs? Although this fundamental question has not been fully addressed yet, research about each organelle has been advancing. The proliferation of the peroxisome is regulated by the PPARα pathway, whereas the abundance of mitochondria appears to be regulated by mitochondrial retrograde signaling and the mitochondrial unfolded protein response. The functional capacity of the Golgi apparatus may be regulated by the mechanism of the Golgi stress response. These observations strongly suggest the existence of an elaborate network of organelle autoregulation in eukaryotic cells. © 2009 IUBMB IUBMB Life 61(9): 871–879, 2009

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Saccharomyces cerevisiae PIP2 Mediating Oleic Acid Induction and Peroxisome Proliferation Is Regulated by Adr1p and Pip2p-Oaf1p

Cited by 26 publications

References 52 publications

Mxr1p, a Key Regulator of the Methanol Utilization Pathway and Peroxisomal Genes in Pichia pastoris

Mxr1p, a Key Regulator of the Methanol Utilization Pathway and Peroxisomal Genes in Pichia pastoris

Regulatory Genes Controlling Fatty Acid Catabolism and Peroxisomal Functions in the Filamentous Fungus Aspergillus nidulans

ER stress response, peroxisome proliferation, mitochondrial unfolded protein response and Golgi stress response

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