Membrane Rafts Are Involved in Intracellular Miconazole Accumulation in Yeast Cells
Azoles inhibit ergosterol biosynthesis, resulting in ergosterol depletion and accumulation of toxic 14α-methylated sterols in membranes of susceptible yeast. We demonstrated previously that miconazole induces actin cytoskeleton stabilization in Saccharomyces cerevisiae prior to induction of reactive...
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| Veröffentlicht in: | The Journal of biological chemistry 2009-11, Vol.284 (47), p.32680-32685 |
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| creator | François, Isabelle E.J.A. Bink, Anna Vandercappellen, Jo Ayscough, Kathryn R. Toulmay, Alexandre Schneiter, Roger van Gyseghem, Elke Van den Mooter, Guy Borgers, Marcel Vandenbosch, Davy Coenye, Tom Cammue, Bruno P.A. Thevissen, Karin |
| description | Azoles inhibit ergosterol biosynthesis, resulting in ergosterol depletion and accumulation of toxic 14α-methylated sterols in membranes of susceptible yeast. We demonstrated previously that miconazole induces actin cytoskeleton stabilization in Saccharomyces cerevisiae prior to induction of reactive oxygen species, pointing to an ancillary mode of action. Using a genome-wide agar-based screening, we demonstrate in this study that S. cerevisiae mutants affected in sphingolipid and ergosterol biosynthesis, namely ipt1, sur1, skn1, and erg3 deletion mutants, are miconazole-resistant, suggesting an involvement of membrane rafts in its mode of action. This is supported by the antagonizing effect of membrane raft-disturbing compounds on miconazole antifungal activity as well as on miconazole-induced actin cytoskeleton stabilization and reactive oxygen species accumulation. These antagonizing effects point to a primary role for membrane rafts in miconazole antifungal activity. We further show that this primary role of membrane rafts in miconazole action consists of mediating intracellular accumulation of miconazole in yeast cells. |
| doi_str_mv | 10.1074/jbc.M109.014571 |
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We demonstrated previously that miconazole induces actin cytoskeleton stabilization in Saccharomyces cerevisiae prior to induction of reactive oxygen species, pointing to an ancillary mode of action. Using a genome-wide agar-based screening, we demonstrate in this study that S. cerevisiae mutants affected in sphingolipid and ergosterol biosynthesis, namely ipt1, sur1, skn1, and erg3 deletion mutants, are miconazole-resistant, suggesting an involvement of membrane rafts in its mode of action. This is supported by the antagonizing effect of membrane raft-disturbing compounds on miconazole antifungal activity as well as on miconazole-induced actin cytoskeleton stabilization and reactive oxygen species accumulation. These antagonizing effects point to a primary role for membrane rafts in miconazole antifungal activity. We further show that this primary role of membrane rafts in miconazole action consists of mediating intracellular accumulation of miconazole in yeast cells.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M109.014571</identifier><identifier>PMID: 19783660</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antifungal Agents - pharmacokinetics ; Drug Resistance, Fungal ; Endocytosis ; Ergosterol - metabolism ; Gene Deletion ; Gene Expression Regulation, Fungal ; Genome, Fungal ; Lipids and Lipoproteins: Metabolism, Regulation, and Signaling ; Membrane Microdomains - drug effects ; Membrane Microdomains - metabolism ; Miconazole - pharmacokinetics ; Miconazole - pharmacology ; Phosphodiesterase Inhibitors - pharmacology ; Phospholipid Ethers - pharmacology ; Reactive Oxygen Species ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae - metabolism</subject><ispartof>The Journal of biological chemistry, 2009-11, Vol.284 (47), p.32680-32685</ispartof><rights>2009 © 2009 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2009 by The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-34abf27bc344fca57f17aff49fecf3baec11c9b9cf490b9a35f8141f219db5743</citedby><cites>FETCH-LOGICAL-c592t-34abf27bc344fca57f17aff49fecf3baec11c9b9cf490b9a35f8141f219db5743</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781683/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781683/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19783660$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>François, Isabelle E.J.A.</creatorcontrib><creatorcontrib>Bink, Anna</creatorcontrib><creatorcontrib>Vandercappellen, Jo</creatorcontrib><creatorcontrib>Ayscough, Kathryn R.</creatorcontrib><creatorcontrib>Toulmay, Alexandre</creatorcontrib><creatorcontrib>Schneiter, Roger</creatorcontrib><creatorcontrib>van Gyseghem, Elke</creatorcontrib><creatorcontrib>Van den Mooter, Guy</creatorcontrib><creatorcontrib>Borgers, Marcel</creatorcontrib><creatorcontrib>Vandenbosch, Davy</creatorcontrib><creatorcontrib>Coenye, Tom</creatorcontrib><creatorcontrib>Cammue, Bruno P.A.</creatorcontrib><creatorcontrib>Thevissen, Karin</creatorcontrib><title>Membrane Rafts Are Involved in Intracellular Miconazole Accumulation in Yeast Cells</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Azoles inhibit ergosterol biosynthesis, resulting in ergosterol depletion and accumulation of toxic 14α-methylated sterols in membranes of susceptible yeast. We demonstrated previously that miconazole induces actin cytoskeleton stabilization in Saccharomyces cerevisiae prior to induction of reactive oxygen species, pointing to an ancillary mode of action. Using a genome-wide agar-based screening, we demonstrate in this study that S. cerevisiae mutants affected in sphingolipid and ergosterol biosynthesis, namely ipt1, sur1, skn1, and erg3 deletion mutants, are miconazole-resistant, suggesting an involvement of membrane rafts in its mode of action. This is supported by the antagonizing effect of membrane raft-disturbing compounds on miconazole antifungal activity as well as on miconazole-induced actin cytoskeleton stabilization and reactive oxygen species accumulation. These antagonizing effects point to a primary role for membrane rafts in miconazole antifungal activity. We further show that this primary role of membrane rafts in miconazole action consists of mediating intracellular accumulation of miconazole in yeast cells.</description><subject>Antifungal Agents - pharmacokinetics</subject><subject>Drug Resistance, Fungal</subject><subject>Endocytosis</subject><subject>Ergosterol - metabolism</subject><subject>Gene Deletion</subject><subject>Gene Expression Regulation, Fungal</subject><subject>Genome, Fungal</subject><subject>Lipids and Lipoproteins: Metabolism, Regulation, and Signaling</subject><subject>Membrane Microdomains - drug effects</subject><subject>Membrane Microdomains - metabolism</subject><subject>Miconazole - pharmacokinetics</subject><subject>Miconazole - pharmacology</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Phospholipid Ethers - pharmacology</subject><subject>Reactive Oxygen Species</subject><subject>Saccharomyces cerevisiae</subject><subject>Saccharomyces cerevisiae - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc-P1CAUx4nRuOPq2Zv2YLx1lge0lIvJZOLqJjsxcd1ETwQozLBpywrtmPWvl6YTfxzkAnl8-L7H94vQS8BrwJxd3Gmz3gEWawys4vAIrQA3tKQVfH2MVhgTKAWpmjP0LKU7nBcT8BSdgeANrWu8Qjc72-uoBlt8Vm5MxSba4mo4hu5o28IP-TxGZWzXTZ2Kxc6bMKifobPFxpipz8XRh2EGv1mVxmKbyfQcPXGqS_bFaT9Ht5fvv2w_ltefPlxtN9elqQQZS8qUdoRrQxlzRlXcAVfOMeGscVQrawCM0MLkEtZC0co1wMAREK2uOKPn6N2iez_p3rbGzrN28j76XsUHGZSX_94M_iD34SgJb6BuaBZ4exKI4ftk0yh7n-bPZj_ClCQB4LziIoMXC2hiSCla97sJYDkHIXMQcg5CLkHkF6_-nu0Pf3I-A28W4OD3hx8-Wql9MAfbS9IwybikpG5m7PWCORWk2kef5O0NwUAxcEzqenZBLITNVh-9jTIZbwdj2yxqRtkG_98pfwEnO67T</recordid><startdate>20091120</startdate><enddate>20091120</enddate><creator>François, Isabelle E.J.A.</creator><creator>Bink, Anna</creator><creator>Vandercappellen, Jo</creator><creator>Ayscough, Kathryn R.</creator><creator>Toulmay, Alexandre</creator><creator>Schneiter, Roger</creator><creator>van Gyseghem, Elke</creator><creator>Van den Mooter, Guy</creator><creator>Borgers, Marcel</creator><creator>Vandenbosch, Davy</creator><creator>Coenye, Tom</creator><creator>Cammue, Bruno P.A.</creator><creator>Thevissen, Karin</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U7</scope><scope>C1K</scope><scope>M7N</scope><scope>5PM</scope></search><sort><creationdate>20091120</creationdate><title>Membrane Rafts Are Involved in Intracellular Miconazole Accumulation in Yeast Cells</title><author>François, Isabelle E.J.A. ; Bink, Anna ; Vandercappellen, Jo ; Ayscough, Kathryn R. ; Toulmay, Alexandre ; Schneiter, Roger ; van Gyseghem, Elke ; Van den Mooter, Guy ; Borgers, Marcel ; Vandenbosch, Davy ; Coenye, Tom ; Cammue, Bruno P.A. ; Thevissen, Karin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-34abf27bc344fca57f17aff49fecf3baec11c9b9cf490b9a35f8141f219db5743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Antifungal Agents - pharmacokinetics</topic><topic>Drug Resistance, Fungal</topic><topic>Endocytosis</topic><topic>Ergosterol - metabolism</topic><topic>Gene Deletion</topic><topic>Gene Expression Regulation, Fungal</topic><topic>Genome, Fungal</topic><topic>Lipids and Lipoproteins: Metabolism, Regulation, and Signaling</topic><topic>Membrane Microdomains - drug effects</topic><topic>Membrane Microdomains - metabolism</topic><topic>Miconazole - pharmacokinetics</topic><topic>Miconazole - pharmacology</topic><topic>Phosphodiesterase Inhibitors - pharmacology</topic><topic>Phospholipid Ethers - pharmacology</topic><topic>Reactive Oxygen Species</topic><topic>Saccharomyces cerevisiae</topic><topic>Saccharomyces cerevisiae - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>François, Isabelle E.J.A.</creatorcontrib><creatorcontrib>Bink, Anna</creatorcontrib><creatorcontrib>Vandercappellen, Jo</creatorcontrib><creatorcontrib>Ayscough, Kathryn R.</creatorcontrib><creatorcontrib>Toulmay, Alexandre</creatorcontrib><creatorcontrib>Schneiter, Roger</creatorcontrib><creatorcontrib>van Gyseghem, Elke</creatorcontrib><creatorcontrib>Van den Mooter, Guy</creatorcontrib><creatorcontrib>Borgers, Marcel</creatorcontrib><creatorcontrib>Vandenbosch, Davy</creatorcontrib><creatorcontrib>Coenye, Tom</creatorcontrib><creatorcontrib>Cammue, Bruno P.A.</creatorcontrib><creatorcontrib>Thevissen, Karin</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>François, Isabelle E.J.A.</au><au>Bink, Anna</au><au>Vandercappellen, Jo</au><au>Ayscough, Kathryn R.</au><au>Toulmay, Alexandre</au><au>Schneiter, Roger</au><au>van Gyseghem, Elke</au><au>Van den Mooter, Guy</au><au>Borgers, Marcel</au><au>Vandenbosch, Davy</au><au>Coenye, Tom</au><au>Cammue, Bruno P.A.</au><au>Thevissen, Karin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Membrane Rafts Are Involved in Intracellular Miconazole Accumulation in Yeast Cells</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2009-11-20</date><risdate>2009</risdate><volume>284</volume><issue>47</issue><spage>32680</spage><epage>32685</epage><pages>32680-32685</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Azoles inhibit ergosterol biosynthesis, resulting in ergosterol depletion and accumulation of toxic 14α-methylated sterols in membranes of susceptible yeast. We demonstrated previously that miconazole induces actin cytoskeleton stabilization in Saccharomyces cerevisiae prior to induction of reactive oxygen species, pointing to an ancillary mode of action. Using a genome-wide agar-based screening, we demonstrate in this study that S. cerevisiae mutants affected in sphingolipid and ergosterol biosynthesis, namely ipt1, sur1, skn1, and erg3 deletion mutants, are miconazole-resistant, suggesting an involvement of membrane rafts in its mode of action. This is supported by the antagonizing effect of membrane raft-disturbing compounds on miconazole antifungal activity as well as on miconazole-induced actin cytoskeleton stabilization and reactive oxygen species accumulation. These antagonizing effects point to a primary role for membrane rafts in miconazole antifungal activity. 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Antifungal Agents - pharmacokinetics Drug Resistance, Fungal Endocytosis Ergosterol - metabolism Gene Deletion Gene Expression Regulation, Fungal Genome, Fungal Lipids and Lipoproteins: Metabolism, Regulation, and Signaling Membrane Microdomains - drug effects Membrane Microdomains - metabolism Miconazole - pharmacokinetics Miconazole - pharmacology Phosphodiesterase Inhibitors - pharmacology Phospholipid Ethers - pharmacology Reactive Oxygen Species Saccharomyces cerevisiae Saccharomyces cerevisiae - metabolism |
| title | Membrane Rafts Are Involved in Intracellular Miconazole Accumulation in Yeast Cells |
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