The role of sigma 1 receptor in organization of endoplasmic reticulum signaling microdomains.
cell biology
cholesterol
endoplasmic reticulum
human
lipid microdomains
mitochondria-associated membranes
neurodegeneration
neuroscience
sigma-1 receptor
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
11 05 2021
11 05 2021
Historique:
received:
25
11
2020
accepted:
29
04
2021
entrez:
11
5
2021
pubmed:
12
5
2021
medline:
20
2
2022
Statut:
epublish
Résumé
Sigma 1 receptor (S1R) is a 223-amino-acid-long transmembrane endoplasmic reticulum (ER) protein. S1R modulates activity of multiple effector proteins and is a well-established drug target. However, signaling functions of S1R in cells are poorly understood. Here, we test the hypothesis that biological activity of S1R in cells can be explained by its ability to interact with cholesterol and to form cholesterol-enriched microdomains in the ER membrane. By performing experiments in reduced reconstitution systems, we demonstrate direct effects of cholesterol on S1R clustering. We identify a novel cholesterol-binding motif in the transmembrane region of human S1R. Mutations of this motif impair association of recombinant S1R with cholesterol beads, affect S1R clustering in vitro and disrupt S1R subcellular localization. We demonstrate that S1R-induced membrane microdomains have increased local membrane thickness and that increased local cholesterol concentration and/or membrane thickness in these microdomains can modulate signaling of inositol-requiring enzyme 1α in the ER. Further, S1R agonists cause disruption of S1R clusters, suggesting that biological activity of S1R agonists is linked to remodeling of ER membrane microdomains. Our results provide novel insights into S1R-mediated signaling mechanisms in cells.
Identifiants
pubmed: 33973848
doi: 10.7554/eLife.65192
pii: 65192
pmc: PMC8112866
doi:
pii:
Substances chimiques
Receptors, sigma
0
Cholesterol
97C5T2UQ7J
Banques de données
Dryad
['10.5061/dryad.9zw3r22dn']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM113079
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS056224
Pays : United States
Informations de copyright
© 2021, Zhemkov et al.
Déclaration de conflit d'intérêts
VZ, JD, WL, MW, JL, MR, IB No competing interests declared
Références
J Mol Cell Biol. 2021 Feb 03;:
pubmed: 33532844
FEBS Lett. 2004 Feb 13;559(1-3):145-51
pubmed: 14960323
Mol Cell Neurosci. 2013 Jul;55:26-36
pubmed: 22922446
Comput Struct Biotechnol J. 2020 Jan 07;18:199-206
pubmed: 32055286
Cells. 2019 Mar 02;8(3):
pubmed: 30832324
Adv Exp Med Biol. 2017;964:133-152
pubmed: 28315269
Handb Exp Pharmacol. 2017;244:109-130
pubmed: 28275909
Nat Commun. 2020 Nov 4;11(1):5580
pubmed: 33149115
Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11411-6
pubmed: 21709267
Anal Chem. 2015 Sep 15;87(18):9194-203
pubmed: 26268463
Trends Neurosci. 2012 Dec;35(12):762-71
pubmed: 23102998
Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14949-54
pubmed: 15466698
Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3654-8
pubmed: 19225105
Front Neurosci. 2019 Aug 28;13:862
pubmed: 31551669
Br J Pharmacol. 2021 Mar;178(6):1336-1352
pubmed: 32761823
J Pharmacol Exp Ther. 2003 Aug;306(2):726-33
pubmed: 12730356
EMBO J. 2020 Oct 15;39(20):e103791
pubmed: 32865299
Cell Rep. 2016 May 24;15(8):1837-47
pubmed: 27184847
Neuropharmacology. 2018 May 1;133:264-275
pubmed: 29407216
Traffic. 2011 Jan;12(1):28-41
pubmed: 20955502
Front Physiol. 2015 Mar 19;6:89
pubmed: 25852575
Trends Pharmacol Sci. 2010 Dec;31(12):557-66
pubmed: 20869780
J Pharmacol Exp Ther. 2003 Aug;306(2):718-25
pubmed: 12730355
Cancer Res. 2007 Dec 1;67(23):11166-75
pubmed: 18056441
Invest Ophthalmol Vis Sci. 2017 Sep 1;58(11):4545-4558
pubmed: 28877319
Cell Rep. 2013 Nov 14;5(3):813-25
pubmed: 24183667
Nat Rev Mol Cell Biol. 2008 Feb;9(2):112-24
pubmed: 18216768
Biochem J. 2015 Mar 1;466(2):263-271
pubmed: 25510962
Science. 2016 Apr 29;352(6285):595-9
pubmed: 27056844
Handb Exp Pharmacol. 2017;244:81-108
pubmed: 28275911
Front Neurosci. 2019 Dec 19;13:1356
pubmed: 31920515
Neoplasia. 2018 May;20(5):510-523
pubmed: 29626751
EMBO J. 2017 Nov 15;36(22):3356-3371
pubmed: 29018038
Cell Mol Neurobiol. 2020 Oct 23;:
pubmed: 33095392
Nat Biotechnol. 2016 Sep;34(9):987-92
pubmed: 27376584
Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16628-33
pubmed: 21930944
Front Neurosci. 2019 Jul 16;13:733
pubmed: 31379486
Nat Protoc. 2009;4(11):1582-90
pubmed: 19816421
Cell Rep. 2019 Apr 2;27(1):307-320.e5
pubmed: 30943411
Biochemistry. 2011 Nov 29;50(47):10367-74
pubmed: 21992175
Nat Commun. 2015 Jan 30;6:5984
pubmed: 25635869
Mol Cell. 2017 Aug 17;67(4):673-684.e8
pubmed: 28689662
Lancet Neurol. 2019 Feb;18(2):165-176
pubmed: 30563778
Protein Cell. 2018 Aug;9(8):733-737
pubmed: 28929457
EMBO J. 2012 Nov 5;31(21):4106-23
pubmed: 22892566
Cell. 2015 Mar 26;161(1):161-172
pubmed: 25815993
PLoS One. 2013 Oct 18;8(10):e76941
pubmed: 24204710
Sci Adv. 2020 Nov 11;6(46):
pubmed: 33177076
Nat Cell Biol. 2003 Sep;5(9):781-92
pubmed: 12907943
Nat Commun. 2017 Oct 31;8(1):1219
pubmed: 29089556
Neurology. 2016 Oct 11;87(15):1607-1612
pubmed: 27629094
Nat Protoc. 2016 Mar;11(3):456-75
pubmed: 26866790
Trends Cell Biol. 2018 Jul;28(7):523-540
pubmed: 29588129
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11041-8
pubmed: 10500120
Oncotarget. 2017 May 16;8(31):51317-51330
pubmed: 28881650
EMBO Mol Med. 2016 Dec 1;8(12):1421-1437
pubmed: 27821430
J Phys Chem B. 2019 Aug 1;123(30):6492-6504
pubmed: 31290322
Biophys J. 2003 Aug;85(2):933-42
pubmed: 12885640
Neurobiol Dis. 2017 Jan;97(Pt A):46-59
pubmed: 27818324
J Am Chem Soc. 2009 Feb 11;131(5):1810-9
pubmed: 19154115
Sci Transl Med. 2019 Feb 6;11(478):
pubmed: 30728287
Expert Opin Ther Targets. 2020 Oct;24(10):1009-1028
pubmed: 32746649
J Biol Chem. 2004 Aug 27;279(35):37030-9
pubmed: 15215242
Hum Mol Genet. 2016 Sep 1;25(17):3741-3753
pubmed: 27402882
Acta Myol. 2018 May 01;37(1):2-4
pubmed: 30079398
J Cell Biol. 2016 Apr 11;213(1):65-79
pubmed: 27069021
Neuron. 2002 Apr 25;34(3):399-410
pubmed: 11988171
J Med Genet. 2020 Mar;57(3):178-186
pubmed: 31511340
Mol Pharmacol. 2007 Oct;72(4):921-33
pubmed: 17622576
Cell Death Dis. 2014 Jun 12;5:e1290
pubmed: 24922074
Ann Neurol. 2011 Dec;70(6):913-9
pubmed: 21842496
Cell Calcium. 2002 Nov-Dec;32(5-6):363-77
pubmed: 12543096
Neuroscience. 2013 Jun 14;240:129-34
pubmed: 23458708
Nat Methods. 2014 Aug;11(8):783-784
pubmed: 25075903
J Pharmacol Exp Ther. 2020 May;373(2):290-301
pubmed: 32060048
Trends Pharmacol Sci. 2019 Sep;40(9):636-654
pubmed: 31387763
Cell Metab. 2008 Dec;8(6):512-21
pubmed: 19041766
Nature. 2016 Apr 28;532(7600):527-30
pubmed: 27042935
Mol Cell. 2009 Nov 13;36(3):500-11
pubmed: 19917257
Cell. 2007 Nov 2;131(3):596-610
pubmed: 17981125
Trends Pharmacol Sci. 2016 Apr;37(4):262-278
pubmed: 26869505
J Microsc. 2006 Dec;224(Pt 3):213-32
pubmed: 17210054
Handb Exp Pharmacol. 2017;244:237-308
pubmed: 28744586
Compr Physiol. 2012 Jan;2(1):31-68
pubmed: 23728970
Nature. 1979 Jun 7;279(5713):538-41
pubmed: 156308
Pharmacol Ther. 2009 Nov;124(2):195-206
pubmed: 19619582
Biotechniques. 2007 Jul;43(1 Suppl):25-30
pubmed: 17936939
Nat Methods. 2013 Mar;10(3):259-64
pubmed: 23396283
Nat Rev Mol Cell Biol. 2017 Jun;18(6):361-374
pubmed: 28356571
Biochim Biophys Acta. 2014 Apr 4;1841(4):595-609
pubmed: 24316057
Cell Death Dis. 2018 Feb 28;9(3):328
pubmed: 29491402
Neurobiol Aging. 2017 Nov;59:171-183
pubmed: 28870519
Neurology. 2015 Jun 16;84(24):2430-7
pubmed: 26078401
Nat Rev Mol Cell Biol. 2020 Jan;21(1):7-24
pubmed: 31732717
Nature. 2002 Jan 3;415(6867):92-6
pubmed: 11780124
J Membr Biol. 2005 Dec;208(3):193-202
pubmed: 16604469
Nat Commun. 2020 Feb 6;11(1):756
pubmed: 32029718
Front Physiol. 2013 Feb 28;4:31
pubmed: 23450735
Trends Cell Biol. 2020 May;30(5):341-353
pubmed: 32302547
Adv Exp Med Biol. 2020;1131:699-718
pubmed: 31646531
Mol Pharmacol. 2010 Apr;77(4):517-28
pubmed: 20053954
Autophagy. 2016 Jun 2;12(6):917-35
pubmed: 27123544
J Biol Chem. 2014 Jul 18;289(29):20333-44
pubmed: 24847081
Langmuir. 2016 Mar 29;32(12):2963-74
pubmed: 26812542
Cell. 2010 Jul 9;142(1):158-69
pubmed: 20603021
Proc Natl Acad Sci U S A. 2020 Mar 31;117(13):7225-7235
pubmed: 32179693
J Biol Chem. 2017 Jul 7;292(27):11250-11261
pubmed: 28495886