ArticleProceedings of the National Academy of Sciences of the United States of America2011
Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 172 papers.
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172 citing papers in PubMed, 289 citations in OpenAlex.
- Compound Z247611722 Exhibits Antifungal Activity by Inhibiting Serine Palmitoyltransferase.Nature communications · 2026Article
- Candida glabrata YPK2 is a multidrug susceptibility locus.Genetics · 2026Article
- Article
- Uncoupling of nutrient sensing and cell size control by specific defects in ceramide structure.Biology open · 2026Article
- Intersection of Sphingolipid and Sterol Metabolism at the Level of Orm Proteins in Yeast.Cells · 2026Article
- ORMDL Proteins Turnover via Proteasome and Autophagy Is Cell-Type Dependent and Tied to Ceramide Homeostasis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- An mTORC2-Lipid Signaling Axis Controls Stress-Induced Organismal Death.Research square · 2026Article
- Impairment of ribosomes and DNA biosynthesis confers resistance to Inhibition of sphingolipid biosynthesis.Molecular genetics and genomics : MGG · 2026Article
- Orm2 promotes nitrogen-induced sphingolipid production and endocytosis via Orm1 phosphorylation.Journal of lipid research · 2025Article
- A growing problem: The many unsolved mysteries of cell growth.Molecular biology of the cell · 2025Review
- Intricate Regulation of Sphingolipid Biosynthesis: An In-Depth Look Into ORMDL-Mediated Regulation of Serine Palmitoyltransferase.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Sugar accelerates chronological aging in yeast via ceramides.Cell stress · 2025Review
- Stress granule formation is regulated by signaling machinery involving Sch9/Ypk1, sphingolipids, and Ubi4.Theranostics · 2025Article
- Biological Importance of Complex Sphingolipids and Their Structural Diversity in Budding YeastInternational journal of molecular sciences · 2024Review
- The Dsc complex and its role in Golgi quality control.Biochemical Society transactions · 2024Review
- Regulation of cellular and systemic sphingolipid homeostasis.Nature reviews. Molecular cell biology · 2024Review
- Ceramides are fuel gauges on the drive to cardiometabolic disease.Physiological reviews · 2024Review
- Activation of the cell wall integrity pathway negatively regulates TORC2-Ypk1/2 signaling through blocking eisosome disassembly in Saccharomyces cerevisiae.Communications biology · 2024Article
- Three kingdoms and one ceramide to rule them all. A comparison of the structural basis of ceramide-dependent regulation of sphingolipid biosynthesis in animals, plants, and fungi.Advances in biological regulation · 2024Article
- Structure of the ceramide-bound SPOTS complex.Nature communications · 2023Article
112 more citing papers are in PubMed but not listed here.
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5 authors at 3 institutions in 1 country.
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Abstract
The Orm family proteins are conserved integral membrane proteins of the endoplasmic reticulum that are key homeostatic regulators of sphingolipid biosynthesis. Orm proteins bind to and inhibit serine:palmitoyl-coenzyme A transferase, the first enzyme in sphingolipid biosynthesis. In Saccharomyces cerevisiae, Orm1 and Orm2 are inactivated by phosphorylation in response to compromised sphingolipid synthesis (e.g., upon addition of inhibitor myriocin), thereby restoring sphingolipid production. We show here that protein kinase Ypk1, one of an essential pair of protein kinases, is responsible for this regulatory modification. Myriocin-induced hyperphosphorylation of Orm1 and Orm2 does not occur in ypk1 cells, and immunopurified Ypk1 phosphorylates Orm1 and Orm2 robustly in vitro exclusively on three residues that are known myriocin-induced sites. Furthermore, the temperature-sensitive growth of ypk1(ts) ypk2 cells is substantially ameliorated by deletion of ORM genes, confirming that a primary physiological role of Ypk1-mediated phosphorylation is to negatively regulate Orm function. Ypk1 immunoprecipitated from myriocin-treated cells displays a higher specific activity for Orm phosphorylation than Ypk1 from untreated cells. To identify the mechanism underlying Ypk1 activation, we systematically tested several candidate factors and found that the target of rapamycin complex 2 (TORC2) kinase plays a key role. In agreement with prior evidence that a TORC2-dependent site in Ypk1(T662) is necessary for cells to exhibit a wild-type level of myriocin resistance, a Ypk1(T662A) mutant displays only weak Orm phosphorylation in vivo and only weak activation in vitro in response to sphingolipid depletion. Additionally, sphingolipid depletion increases phosphorylation of Ypk1 at T662. Thus, Ypk1 is both a sensor and effector of sphingolipid level, and reduction in sphingolipids stimulates Ypk1, at least in part, via TORC2-dependent phosphorylation.
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