Cited by 60Fungal and yeast genetics researchCancer, Lipids, and MetabolismCholesterol and Lipid Metabolism

4-Methyl sterols regulate fission yeast SREBP-Scap under low oxygen and cell stress.

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Hughes, Adam L., Lee, Chih-Yung S., Bien, Clara M., Espenshade, Peter J.·2007·Journal of Biological Chemistry

Abstract

In fission yeast, orthologs of mammalian SREBP and Scap, called Sre1 and Scp1, monitor oxygen-dependent sterol synthesis as a measure of cellular oxygen supply. Under low oxygen conditions, sterol synthesis is inhibited, and Sre1 cleavage is activated. However, the sterol signal for Sre1 activation is unknown. In this study, we characterized the sterol signal for Sre1 activation using a combination of Sre1 cleavage assays and gas chromatography sterol analysis. We find that Sre1 activation is regulated by levels of the 4-methyl sterols 24-methylene lanosterol and 4,4-dimethylfecosterol under conditions of low oxygen and cell stress. Both increases and decreases in the level of these ergosterol pathway intermediates induce Sre1 proteolysis in a Scp1-dependent manner. The SREBP ortholog in the pathogenic fungus Cryptococcus neoformans is also activated by high levels of 4-methyl sterols, suggesting that this signal for SREBP activation is conserved among unicellular eukaryotes. Finally, we provide evidence that the sterol-sensing domain of Scp1 is important for regulating Sre1 proteolysis. The conserved mutations Y247C, L264F, and D392N in Scp1 that render Scap insensitive to sterols cause constitutive Sre1 activation. These findings indicate that unlike Scap, fission yeast Scp1 responds to 4-methyl sterols and thus shares properties with mammalian HMG-CoA reductase, a sterol-sensing domain protein whose degradation is regulated by the 4-methyl sterol lanosterol.

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  1. Yabe, D., Xia, Z. P., Adams, C. M., and Rawson, R. B. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 16672-16677
  2. Adams, C. M., Goldstein, J. L., and Brown, M. S. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 10647-10652

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Authors
Hughes, A. L., Lee, C.-Y. S., Bien, C. M., & Espenshade, P. J.
Affiliations
Johns Hopkins University (US)
Corresponding author
Espenshade, Peter J.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2007-08
Volume
282
Issue
33
Pages
24388-24396
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2126268158
Cited by
60
References
26
Citations by year
2025: 4 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 1 · 2017: 4 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 4
FWCI
2.39
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Heart Association
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL077588, HL 077588)
  • National Institute of General Medical Sciences (GM007445, T32GM007445)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
SREBP, SCP1, hypoxia, cellular stress, sterol sensing, sterol biosynthesis, Cryptococcus neoformans, Schizosaccharomyces pombe, HMG-CoA reductase, sterol-sensing domain, oxygen sensing
MeSH terms
Lanosterol, Mutation, Oxygen, Schizosaccharomyces, Sterols, Gene Expression Regulation, Fungal, Oxidative Stress, Sterol Regulatory Element Binding Proteins

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