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Ergosterol regulates sterol regulatory element binding protein (SREBP) cleavage in fission yeast.

ABSTRACT: In fission yeast, the endoplasmic reticulum membrane-bound proteins Sre1 and Scp1, orthologs of mammalian sterol regulatory element binding protein (SREBP) and Scap, monitor sterol synthesis as an indirect measure of oxygen supply. When cellular oxygen levels are low, sterol synthesis is inhibited, and the Sre1-Scp1 complex responds by increasing transcription of genes required for adaptation to hypoxia. Sre1 and Scp1 are believed to detect a blockage in sterol synthesis by monitoring levels of particular sterols, but the evidence concerning which sterol signals this condition is unclear. Here, we demonstrate that Sre1-Scp1 senses ergosterol. Processing experimental data with a mathematical model of Sre1 and Scp1 function reveals a clear quantitative relationship between ergosterol concentration in the endoplasmic reticulum and Sre1 activation. Based on this relationship, we predict that the Sre1-Scp1 complex exists under "active" and "inactive" states and that the transition between these states is cooperatively mediated by ergosterol.

SUBMITTER: Porter JR

PROVIDER: S-EPMC3003404 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Ergosterol regulates sterol regulatory element binding protein (SREBP) cleavage in fission yeast.

Porter Joshua R JR Burg John S JS Espenshade Peter J PJ Iglesias Pablo A PA

The Journal of biological chemistry 20101019 52

In fission yeast, the endoplasmic reticulum membrane-bound proteins Sre1 and Scp1, orthologs of mammalian sterol regulatory element binding protein (SREBP) and Scap, monitor sterol synthesis as an indirect measure of oxygen supply. When cellular oxygen levels are low, sterol synthesis is inhibited, and the Sre1-Scp1 complex responds by increasing transcription of genes required for adaptation to hypoxia. Sre1 and Scp1 are believed to detect a blockage in sterol synthesis by monitoring levels of ...[more]

PMID: 20959444

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Project description:Sterol regulatory element-binding protein (SREBP), a highly conserved family of membrane-bound transcription factors, is an essential regulator for cellular cholesterol and lipid homeostasis in mammalian cells. Sre1, the homolog of SREBP in the fission yeast Schizosaccharomyces pombe (S. pombe), regulates genes involved in the transcriptional responses to low sterol as well as low oxygen. Previous study reported that casein kinase 1 family member Hhp2 phosphorylated the Sre1 N-terminal transcriptional factor domain (Sre1N) and accelerated Sre1N degradation, and other kinases might exist for regulating the Sre1 function. To gain insight into the mechanisms underlying the Sre1 activity and to identify additional kinases involved in regulation of Sre1 function, we developed a luciferase reporter system to monitor the Sre1 activity through its binding site called SRE2 in living yeast cells. Here we showed that both ergosterol biosynthesis inhibitors and hypoxia-mimic CoCl2 caused a dose-dependent increase in the Sre1 transcription activity, concurrently, these induced transcription activities were almost abolished in ?sre1 cells. Surprisingly, either AMPK? Subunit Ssp2 deletion or Glycogen Synthase Kinases Gsk3/Gsk31 double deletion significantly suppressed ergosterol biosynthesis inhibitors- or CoCl2-induced Sre1 activity. Notably, the ?ssp2?gsk3?gsk31 mutant showed further decreased Sre1 activity when compared with their single or double deletion. Consistently, the ?ssp2?gsk3?gsk31 mutant showed more marked temperature sensitivity than any of their single or double deletion. Moreover, the fluorescence of GFP-Sre1N localized at the nucleus in wild-type cells, but significantly weaker nuclear fluorescence of GFP-Sre1N was observed in ?ssp2, ?gsk3?gsk31, ?ssp2?gsk3, ?ssp2?gsk31 or ?ssp2?gsk3?gsk31 cells. On the other hand, the immunoblot showed a dramatic decrease in GST-Sre1N levels in the ?gsk3?gsk31 or the ?ssp2?gsk3?gsk31 cells but not in the ?ssp2 cells. Altogether, our findings suggest that Gsk3/Gsk31 may regulate Sre1N degradation, while Ssp2 may regulate not only the degradation of Sre1N but also its translocation to the nucleus.

Dataset Information

Ergosterol regulates sterol regulatory element binding protein (SREBP) cleavage in fission yeast.

Publications

Ergosterol regulates sterol regulatory element binding protein (SREBP) cleavage in fission yeast.

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