Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency in choline-auxotroph yeast
Bao, Xue; Koorengevel, Martijn C.; Groot Koerkamp, Marian J.A.; Homavar, Amir; Weijn, Amrah; Crielaard, Stefan; Renne, Mike F.; Lorent, Joseph H.; Geerts, Willie J.C.; Surma, Michal A.; Mari, Muriel; Holstege, Frank C.P.; Klose, Christian; de Kroon, Anton I.P.M.
(2021) EMBO Journal, volume 40, issue 20, pp. 1 - 26
(Article)
Abstract
Phosphatidylcholine (PC) is an abundant membrane lipid component in most eukaryotes, including yeast, and has been assigned multiple functions in addition to acting as building block of the lipid bilayer. Here, by isolating S. cerevisiae suppressor mutants that exhibit robust growth in the absence of PC, we show that PC essentiality
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is subject to cellular evolvability in yeast. The requirement for PC is suppressed by monosomy of chromosome XV or by a point mutation in the ACC1 gene encoding acetyl-CoA carboxylase. Although these two genetic adaptations rewire lipid biosynthesis in different ways, both decrease Acc1 activity, thereby reducing average acyl chain length. Consistently, soraphen A, a specific inhibitor of Acc1, rescues a yeast mutant with deficient PC synthesis. In the aneuploid suppressor, feedback inhibition of Acc1 through acyl-CoA produced by fatty acid synthase (FAS) results from upregulation of lipid synthesis. The results show that budding yeast regulates acyl chain length by fine-tuning the activities of Acc1 and FAS and indicate that PC evolved by benefitting the maintenance of membrane fluidity.
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Keywords: Acetyl-CoA Carboxylase/genetics, Chromosomes, Fungal, Fatty Acid Synthases/genetics, Feedback, Physiological, Gene Expression Regulation, Fungal, Lipid Bilayers/chemistry, Lipid Metabolism/genetics, Membrane Fluidity, Membrane Lipids/chemistry, Phosphatidylcholines/deficiency, Point Mutation, Saccharomyces cerevisiae/genetics
ISSN: 0261-4189
Publisher: Nature Publishing Group
Note: Funding Information: We thank Utrecht Sequencing Facility for providing sequencing service and data. Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute and Utrecht University. We thank UMC Utrecht Bioinformatics Expertise Core for data analysis and data handling. The UMC Utrecht Bioinformatics Expertise Core is subsidized by the University Medical Center Utrecht, Center for Molecular Medicine. This research was supported by the Division of Chemical Sciences in the Netherlands, with financial aid from The Netherlands Organization for Scientific Research (711.017.010, XB) and by the China Scholarship Council (grant no. 201204910146, XB). Funding Information: We thank Wouter Beugelink, Tine Michels, Robin Hoogebeen and Linda Markus for help with strain construction, Ivo Renkens, Ies Nijman and Joep de Ligt for WGS assistance, Ger Arkesteijn for FACS assistance, Jingchao Wu and Yifei Lang for assistance with gene editing by CRISPR/Cas9, Robert Reid and Klaus Natter for plasmids, Marc Stadler (Helmholtz Centre for Infection Research, Braunschweig, DE) for a kind gift of Soraphen A, Christoph Thiele for providing ergosterol ester C13:0, Philip Lijnzaad, Henk van den Toorn, and Bas van Breukelen for assistance with the analysis of the mRNA profiling data, and Sepp Kohlwein, Klaus Natter and Harald Hofbauer for valuable discussions. We are indebted to Antoinette Killian and Fulvio Reggiori for critically reading the manuscript. We thank Utrecht Sequencing Facility for providing sequencing service and data. Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute and Utrecht University. We thank UMC Utrecht Bioinformatics Expertise Core for data analysis and data handling. The UMC Utrecht Bioinformatics Expertise Core is subsidized by the University Medical Center Utrecht, Center for Molecular Medicine. This research was supported by the Division of Chemical Sciences in the Netherlands, with financial aid from The Netherlands Organization for Scientific Research (711.017.010, XB) and by the China Scholarship Council (grant no. 201204910146, XB). Publisher Copyright: © 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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