Sphingolipids function as downstream effectors of a fungal PAQF

Nancy Villa, Brian R. Kupchak, Ibon Garitaonandia, Jessica L. Smith, Emilio Alonso, Charlene Alford, L. Ashley Cowart, Yusuf A. Hannun, Thomas J. Lyons

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

The Izh2p protein from Saccharomyces cerevisiae belongs to the newly characterized progestin and adipoQ receptor (PAQR) superfamily of receptors whose mechanism of signal transduction is still unknown. Izh2p functions as a receptor for the plant PR-5 defensin osmotin and has pleiotropic effects on cellular biochemistry. One example of this pleiotropy is the Izh2p-dependent repression of FET3, a gene involved in iron-uptake. Although the physiological purpose of FET3 repression by Izh2p is a matter of speculation, it provides a reporter with which to probe the mechanism of signal transduction by this novel class of receptor. Receptors in the PAQR family share sequence similarity with enzymes involved in ceramide metabolism, which led to the hypothesis that sphingolipids are in-volved in Izh2p-dependent signaling. In this study, we demonstrate that drugs affecting sphingolipid metabolism, such as D-erythro-MAPP and myriocin, inhibit the effect of Izh2p on FET3. We also show that Izh2p causes an increase in steady-state levels of sphingoid base. Moreover, we show that Izh2p-independent increases in sphingoid bases recapitulate the effect of Izh2p on FET3. Finally, our data indicate that the Pkh1p and Pkh2p sphingoid base-sensing kinases are essential components of the Izh2p-dependent signaling pathway. In conclusion, our data indicate that Izh2p produces sphingoid bases and that these bioactive lipids probably function as the second messenger responsible for the effect of Izh2p on FET3.

Original languageEnglish (US)
Pages (from-to)866-875
Number of pages10
JournalMolecular Pharmacology
Volume75
Issue number4
DOIs
StatePublished - Apr 1 2009
Externally publishedYes

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Sphingolipids
Progesterone Receptors
Signal Transduction
Saccharomyces cerevisiae Proteins
Defensins
Ceramides
Second Messenger Systems
Biochemistry
Phosphotransferases
Iron
Lipids
Enzymes
Pharmaceutical Preparations
Genes
thermozymocidin
2-(N-myristoylamino)-1-phenyl-1-propanol

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Villa, N., Kupchak, B. R., Garitaonandia, I., Smith, J. L., Alonso, E., Alford, C., ... Lyons, T. J. (2009). Sphingolipids function as downstream effectors of a fungal PAQF. Molecular Pharmacology, 75(4), 866-875. https://doi.org/10.1124/mol.108.049809

Sphingolipids function as downstream effectors of a fungal PAQF. / Villa, Nancy; Kupchak, Brian R.; Garitaonandia, Ibon; Smith, Jessica L.; Alonso, Emilio; Alford, Charlene; Cowart, L. Ashley; Hannun, Yusuf A.; Lyons, Thomas J.

In: Molecular Pharmacology, Vol. 75, No. 4, 01.04.2009, p. 866-875.

Research output: Contribution to journalArticle

Villa, N, Kupchak, BR, Garitaonandia, I, Smith, JL, Alonso, E, Alford, C, Cowart, LA, Hannun, YA & Lyons, TJ 2009, 'Sphingolipids function as downstream effectors of a fungal PAQF', Molecular Pharmacology, vol. 75, no. 4, pp. 866-875. https://doi.org/10.1124/mol.108.049809
Villa N, Kupchak BR, Garitaonandia I, Smith JL, Alonso E, Alford C et al. Sphingolipids function as downstream effectors of a fungal PAQF. Molecular Pharmacology. 2009 Apr 1;75(4):866-875. https://doi.org/10.1124/mol.108.049809
Villa, Nancy ; Kupchak, Brian R. ; Garitaonandia, Ibon ; Smith, Jessica L. ; Alonso, Emilio ; Alford, Charlene ; Cowart, L. Ashley ; Hannun, Yusuf A. ; Lyons, Thomas J. / Sphingolipids function as downstream effectors of a fungal PAQF. In: Molecular Pharmacology. 2009 ; Vol. 75, No. 4. pp. 866-875.
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