Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency in choline-auxotroph yeast

Xue Bao; Martijn C. Koorengevel; Marian J.A. Groot Koerkamp; Amir Homavar; Amrah Weijn; Stefan Crielaard; Mike F. Renne; Joseph H. Lorent; Willie J.C. Geerts; Michal A. Surma; Muriel Mari; Frank C.P. Holstege; Christian Klose; Anton I.P.M. de Kroon

doi:10.15252/embj.2021107966

Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency in choline-auxotroph yeast

Xue Bao, Martijn C. Koorengevel, Marian J.A. Groot Koerkamp, Amir Homavar, Amrah Weijn, Stefan Crielaard, Mike F. Renne, Joseph H. Lorent, Willie J.C. Geerts, Michal A. Surma, Muriel Mari, Frank C.P. Holstege, Christian Klose, Anton I.P.M. de Kroon^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 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.

Original language	English
Article number	e107966
Pages (from-to)	1-26
Journal	EMBO Journal
Volume	40
Issue number	20
DOIs	https://doi.org/10.15252/embj.2021107966
Publication status	Published - 18 Oct 2021

Bibliographical 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.

Funding

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). 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).

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

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10.15252/embj.2021107966Licence: CC BY-NC-ND

The EMBO Journal - 2021 - Bao - Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency inFinal published version, 3.98 MBLicence: CC BY-NC-ND

Cite this

Bao, X., Koorengevel, M. C., Groot Koerkamp, M. J. A., Homavar, A., Weijn, A., Crielaard, S., Renne, M. F., Lorent, J. H., Geerts, W. J. C., Surma, M. A., Mari, M., Holstege, F. C. P., Klose, C., & de Kroon, A. I. P. M. (2021). Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency in choline-auxotroph yeast. EMBO Journal, 40(20), 1-26. Article e107966. https://doi.org/10.15252/embj.2021107966

@article{f725c44a21d5415684195d62a4a6a579,

title = "Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency in choline-auxotroph yeast",

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 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.",

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",

author = "Xue Bao and Koorengevel, {Martijn C.} and {Groot Koerkamp}, {Marian J.A.} and Amir Homavar and Amrah Weijn and Stefan Crielaard and Renne, {Mike F.} and Lorent, {Joseph H.} and Geerts, {Willie J.C.} and Surma, {Michal A.} and Muriel Mari and Holstege, {Frank C.P.} and Christian Klose and {de Kroon}, {Anton I.P.M.}",

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: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.",

year = "2021",

month = oct,

day = "18",

doi = "10.15252/embj.2021107966",

language = "English",

volume = "40",

pages = "1--26",

journal = "EMBO Journal",

issn = "0261-4189",

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Bao, X , Koorengevel, MC, Groot Koerkamp, MJA, Homavar, A, Weijn, A, Crielaard, S, Renne, MF, Lorent, JH, Geerts, WJC, Surma, MA, Mari, M, Holstege, FCP, Klose, C & de Kroon, AIPM 2021, 'Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency in choline-auxotroph yeast', EMBO Journal, vol. 40, no. 20, e107966, pp. 1-26. https://doi.org/10.15252/embj.2021107966

TY - JOUR

T1 - Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency in choline-auxotroph yeast

AU - Bao, Xue

AU - Koorengevel, Martijn C.

AU - Groot Koerkamp, Marian J.A.

AU - Homavar, Amir

AU - Weijn, Amrah

AU - Crielaard, Stefan

AU - Renne, Mike F.

AU - Lorent, Joseph H.

AU - Geerts, Willie J.C.

AU - Surma, Michal A.

AU - Mari, Muriel

AU - Holstege, Frank C.P.

AU - Klose, Christian

AU - de Kroon, Anton I.P.M.

N1 - 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.

PY - 2021/10/18

Y1 - 2021/10/18

N2 - 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 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.

AB - 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 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.

KW - Acetyl-CoA Carboxylase/genetics

KW - Chromosomes, Fungal

KW - Fatty Acid Synthases/genetics

KW - Feedback, Physiological

KW - Gene Expression Regulation, Fungal

KW - Lipid Bilayers/chemistry

KW - Lipid Metabolism/genetics

KW - Membrane Fluidity

KW - Membrane Lipids/chemistry

KW - Phosphatidylcholines/deficiency

KW - Point Mutation

KW - Saccharomyces cerevisiae/genetics

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U2 - 10.15252/embj.2021107966

DO - 10.15252/embj.2021107966

M3 - Article

C2 - 34520050

AN - SCOPUS:85114780265

SN - 0261-4189

VL - 40

SP - 1

EP - 26

JO - EMBO Journal

JF - EMBO Journal

IS - 20

M1 - e107966

ER -

Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency in choline-auxotroph yeast

Abstract

Bibliographical note

Funding

Keywords

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