title: Sphingolipid signaling mediates iron toxicity.
abstract: Iron constitutes a major source of toxicity due to its ability to generate reactive oxygen species that can damage cellular macromolecules. However, the precise mechanism by which exposure to high iron concentrations results in cellular toxicity remains unknown. Here we identify sphingolipid synthesis and signaling as a major mediator of iron toxicity in S. cerevisiae. Inhibition of sphingolipid synthesis by myriocin treatment or after overexpression of the negative regulator Orm2p confers resistance to high iron. High iron conditions upregulate sphingolipid synthesis, and increasing sphingolipid levels by inactivating Orm2p exacerbates sensitivity to iron. Toxicity is mediated by sphingolipid signaling, as inactivation of the sphingolipid-activated protein kinases Pkh1p and Ypk1p and of the transcription factor Smp1p also enhances resistance to high iron conditions. These results demonstrate an unexpected connection between sphingolipid flux and iron toxicity and show that activation of a signal transduction cascade contributes to iron-mediated cellular toxicity.
authors: Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095-1569, USA.
authors: Yueh-Jung
authors: YJ
authors: Lee
authors: Xinhe
authors: X
authors: Huang
authors: Janette
authors: J
authors: Kropat
authors: Anthony
authors: A
authors: Henras
authors: Sabeeha S
authors: SS
authors: Merchant
authors: Robert C
authors: RC
authors: Dickson
authors: Guillaume F
authors: GF
authors: Chanfreau
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D055786:Gene Knockout Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism; D050296:Microbial Viability / Q000187:drug effects; D018384:Oxidative Stress; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000096:biosynthesis*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D005229:Fatty Acids, Monounsaturated; D026161:MADS Domain Proteins; C548540:Orm2 protein, S cerevisiae; C095725:RLM1 protein, S cerevisiae; C470554:SMP1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013107:Sphingolipids; D014157:Transcription Factors; D007501:Iron; D038362:Glycogen Synthase Kinase 3; C068124:MCK1 protein, S cerevisiae; C001996:thermozymocidin