Steady state analysis of influx and transbilayer distribution of ergosterol in the yeast plasma membrane.
Cholesterol
Endoplasmic reticulum
Ergosterol
Esterification
Flip-flop
Flux
Non-equilibrium
Plasma membrane
Steady state
Sterol
Journal
Theoretical biology & medical modelling
ISSN: 1742-4682
Titre abrégé: Theor Biol Med Model
Pays: England
ID NLM: 101224383
Informations de publication
Date de publication:
15 08 2019
15 08 2019
Historique:
received:
11
03
2019
accepted:
15
07
2019
entrez:
16
8
2019
pubmed:
16
8
2019
medline:
23
2
2020
Statut:
epublish
Résumé
The transbilayer sterol distribution between both plasma membrane (PM) leaflets has long been debated. Recent studies in mammalian cells and in yeast show that the majority of sterol resides in the inner PM leaflet. Since sterol flip-flop in model membranes is rapid and energy-independent, a mechanistic understanding for net enrichment of sterol in one leaflet is lacking. Import of ergosterol in yeast can take place via the ABC transporters Aus1/Pdr11 under anaerobic growth conditions, eventually followed by rapid non-vesicular sterol transport to the endoplasmic reticulum (ER). Little is known about how these transport steps are dynamically coordinated. Here, a kinetic steady state model is presented which considers sterol import via Aus1/Pdr11, sterol flip-flop across the PM, bi-molecular complex formation and intracellular sterol release followed by eventual transport to and esterification of sterol in the ER. The steady state flux is calculated, and a thermodynamic analysis of feasibility is presented. It is shown that the steady state sterol flux across the PM can be entirely controlled by irreversible sterol import via Aus1/Pdr11. The transbilayer sterol flux at steady state is a non-linear function of the chemical potential difference of sterol between both leaflets. Non-vesicular release of sterol on the cytoplasmic side of the PM lowers the attainable sterol enrichment in the inner leaflet. Including complex formation of sterol with phospholipids or proteins can explain several puzzling experimental observations; 1) rapid sterol flip-flop across the PM despite net sterol enrichment in one leaflet, 2) a pronounced steady state sterol gradient between PM and ER despite fast non-vesicular sterol exchange between both compartments and 3) a non-linear dependence of ER sterol on ergosterol abundance in the PM. A steady state model is presented that can account for the observed sterol asymmetry in the yeast PM, the strong sterol gradient between PM and ER and threshold-like expansion of ER sterol for increasing sterol influx into the PM. The model also provides new insight into selective uptake of cholesterol and its homeostasis in mammalian cells, and it provides testable predictions for future experiments.
Sections du résumé
BACKGROUND
The transbilayer sterol distribution between both plasma membrane (PM) leaflets has long been debated. Recent studies in mammalian cells and in yeast show that the majority of sterol resides in the inner PM leaflet. Since sterol flip-flop in model membranes is rapid and energy-independent, a mechanistic understanding for net enrichment of sterol in one leaflet is lacking. Import of ergosterol in yeast can take place via the ABC transporters Aus1/Pdr11 under anaerobic growth conditions, eventually followed by rapid non-vesicular sterol transport to the endoplasmic reticulum (ER). Little is known about how these transport steps are dynamically coordinated.
METHODS
Here, a kinetic steady state model is presented which considers sterol import via Aus1/Pdr11, sterol flip-flop across the PM, bi-molecular complex formation and intracellular sterol release followed by eventual transport to and esterification of sterol in the ER. The steady state flux is calculated, and a thermodynamic analysis of feasibility is presented.
RESULTS
It is shown that the steady state sterol flux across the PM can be entirely controlled by irreversible sterol import via Aus1/Pdr11. The transbilayer sterol flux at steady state is a non-linear function of the chemical potential difference of sterol between both leaflets. Non-vesicular release of sterol on the cytoplasmic side of the PM lowers the attainable sterol enrichment in the inner leaflet. Including complex formation of sterol with phospholipids or proteins can explain several puzzling experimental observations; 1) rapid sterol flip-flop across the PM despite net sterol enrichment in one leaflet, 2) a pronounced steady state sterol gradient between PM and ER despite fast non-vesicular sterol exchange between both compartments and 3) a non-linear dependence of ER sterol on ergosterol abundance in the PM.
CONCLUSIONS
A steady state model is presented that can account for the observed sterol asymmetry in the yeast PM, the strong sterol gradient between PM and ER and threshold-like expansion of ER sterol for increasing sterol influx into the PM. The model also provides new insight into selective uptake of cholesterol and its homeostasis in mammalian cells, and it provides testable predictions for future experiments.
Identifiants
pubmed: 31412941
doi: 10.1186/s12976-019-0108-2
pii: 10.1186/s12976-019-0108-2
pmc: PMC6694696
doi:
Substances chimiques
Lipid Bilayers
0
Phospholipids
0
Ergosterol
Z30RAY509F
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
13Références
PLoS One. 2014 Jul 11;9(7):e98482
pubmed: 25014655
Traffic. 2005 May;6(5):396-412
pubmed: 15813750
EMBO J. 2015 Aug 13;34(16):2117-31
pubmed: 26162625
EMBO J. 2018 Mar 15;37(6):
pubmed: 29467216
J Biol Chem. 2011 Feb 18;286(7):5043-54
pubmed: 21127065
Biochem Soc Trans. 2006 Jun;34(Pt 3):356-8
pubmed: 16709160
Eur J Biochem. 2003 Feb;270(3):415-21
pubmed: 12542691
Nat Commun. 2015 Feb 06;6:6129
pubmed: 25655993
Biophys J. 2002 Mar;82(3):1418-28
pubmed: 11867457
J Biol Chem. 2002 Jan 4;277(1):609-17
pubmed: 11682487
J Biol Chem. 2004 Mar 19;279(12):11273-80
pubmed: 14660649
Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12662-6
pubmed: 16120676
J Biol Chem. 1983 Feb 25;258(4):2284-9
pubmed: 6822559
Biophys J. 2007 Dec 15;93(12):4244-53
pubmed: 17766353
Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11664-7
pubmed: 15289597
Traffic. 2018 Oct;19(10):750-760
pubmed: 29896788
Biochemistry. 1981 May 12;20(10):2893-900
pubmed: 7195733
Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12422-7
pubmed: 11050164
Biochem J. 2004 Jul 1;381(Pt 1):195-202
pubmed: 15035656
J Biol Chem. 1998 Jul 24;273(30):18915-22
pubmed: 9668068
J Clin Invest. 2002 Oct;110(7):891-8
pubmed: 12370264
J Cell Sci. 2015 Apr 1;128(7):1422-33
pubmed: 25663704
Methods Mol Biol. 2019;1949:115-136
pubmed: 30790253
Chem Biol. 2015 Mar 19;22(3):412-25
pubmed: 25794437
J Lipid Res. 1994 Apr;35(4):644-55
pubmed: 8006519
J Biol Chem. 2008 Jan 18;283(3):1445-55
pubmed: 18024962
J Cell Biol. 1985 Aug;101(2):446-53
pubmed: 4040520
Nat Commun. 2017 Nov 9;8(1):1393
pubmed: 29123120
Mol Biol Cell. 2006 Jan;17(1):90-103
pubmed: 16251356
Sci Rep. 2017 Apr 11;7(1):802
pubmed: 28400621
J Biol Chem. 2004 Oct 22;279(43):45226-34
pubmed: 15316012
J Cell Biol. 2009 Dec 14;187(6):889-903
pubmed: 20008566
Biochim Biophys Acta. 2013 Mar;1828(3):932-7
pubmed: 23220446
Traffic. 2018 Mar;19(3):198-214
pubmed: 29282820
Biochim Biophys Acta. 2001 Mar 9;1511(1):1-6
pubmed: 11248199
Chem Phys Lipids. 2016 Jan;194:12-28
pubmed: 26291493
FEMS Yeast Res. 2014 Dec;14(8):1223-33
pubmed: 25331273
Biochim Biophys Acta. 2002 Aug 19;1564(1):1-4
pubmed: 12100988
Biochim Biophys Acta. 2000 Dec 15;1529(1-3):155-63
pubmed: 11111085
J Lipid Res. 1999 Dec;40(12):2264-70
pubmed: 10588952
Trends Cell Biol. 2010 Nov;20(11):680-7
pubmed: 20843692
Elife. 2014 Jun 11;3:
pubmed: 24920391
Cell Rep. 2018 Jul 24;24(4):1037-1049
pubmed: 30044971
Trends Biochem Sci. 2017 Feb;42(2):90-97
pubmed: 27956059
J Biol Chem. 2010 Sep 17;285(38):29480-90
pubmed: 20573965
PLoS One. 2017 Sep 18;12(9):e0184236
pubmed: 28922409
Biochemistry. 2013 Oct 8;52(40):6950-9
pubmed: 24000774
Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10580-5
pubmed: 23754385
Traffic. 2011 Oct;12(10):1341-55
pubmed: 21689253
Mol Biol Cell. 2011 Nov;22(21):4004-15
pubmed: 21900492
Cell. 2019 Feb 21;176(5):1040-1053.e17
pubmed: 30712872
J Biol Chem. 2004 Aug 27;279(35):37030-9
pubmed: 15215242
Traffic. 2017 Jun;18(6):358-361
pubmed: 28371052
Curr Opin Cell Biol. 2006 Aug;18(4):379-85
pubmed: 16806879
Biophys J. 2002 Oct;83(4):2118-25
pubmed: 12324429
FASEB J. 2015 Nov;29(11):4682-94
pubmed: 26220175
Biochemistry. 2000 Jul 18;39(28):8119-24
pubmed: 10889017
Chem Phys Lipids. 2018 Jul;213:48-61
pubmed: 29580834
Biochem J. 1988 Mar 15;250(3):653-8
pubmed: 3390137
Biochim Biophys Acta. 2009 Jul;1791(7):636-45
pubmed: 19286471
Science. 2017 Mar 24;355(6331):1306-1311
pubmed: 28336668
Chem Phys Lipids. 2016 Sep;199:74-93
pubmed: 26874289
Mol Biol Cell. 2009 Jan;20(2):581-8
pubmed: 19019985
Biophys J. 1999 Sep;77(3):1507-17
pubmed: 10465761
J Cell Biol. 2014 Aug 4;206(3):357-66
pubmed: 25070953
Biochemistry. 2005 Apr 19;44(15):5816-26
pubmed: 15823040
Chem Phys Lipids. 2009 Jun;159(2):114-8
pubmed: 19477318
Elife. 2017 Apr 17;6:
pubmed: 28414269
Biophys J. 2014 Nov 18;107(10):2337-44
pubmed: 25418302
J Cell Sci. 2018 Jun 11;131(11):
pubmed: 29678904
Biochim Biophys Acta. 2015 Sep;1848(9):1908-26
pubmed: 26004840
Biophys J. 2002 Sep;83(3):1525-34
pubmed: 12202377
J Biol Chem. 2011 Jun 17;286(24):21835-43
pubmed: 21521689
J Biol Chem. 2002 Sep 6;277(36):32466-72
pubmed: 12077145
Biochem Biophys Res Commun. 2011 Jan 7;404(1):233-8
pubmed: 21110944
Curr Opin Cell Biol. 2018 Aug;53:37-43
pubmed: 29783105
J Biol Chem. 1991 Sep 15;266(26):17040-8
pubmed: 1894601
Nat Commun. 2014 Nov 07;5:5419
pubmed: 25377891
J Biol Chem. 2003 Nov 14;278(46):45563-9
pubmed: 12947110
PLoS Biol. 2018 May 21;16(5):e2003864
pubmed: 29782498
Elife. 2015 May 22;4:
pubmed: 26001273
Biophys J. 2001 Oct;81(4):2257-67
pubmed: 11566796
Cell. 2018 Oct 4;175(2):514-529.e20
pubmed: 30220461
Nature. 2005 Dec 1;438(7068):612-21
pubmed: 16319881
Traffic. 2013 Aug;14(8):912-21
pubmed: 23668914
Biochim Biophys Acta. 2003 Mar 10;1610(2):159-73
pubmed: 12648771