The role of sigma 1 receptor in organization of endoplasmic reticulum signaling microdomains

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 biologic...

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Bibliographic Details
Published in:eLife 2021-05, Vol.10
Main Authors: Zhemkov, Vladimir, Ditlev, Jonathon A, Lee, Wan-Ru, Wilson, Mikaela, Liou, Jen, Rosen, Michael K, Bezprozvanny, Ilya
Format: Article
Language:English
Subjects:
Agonists
Amyotrophic lateral sclerosis
Binding sites
Biological activity
Cell Biology
Cholesterol
Cholesterol - metabolism
Endoplasmic reticulum
Endoplasmic Reticulum - metabolism
Experiments
HEK293 Cells
Humans
Hypotheses
Inositol
Intracellular Membranes - metabolism
lipid microdomains
Lipids
Localization
Membrane Microdomains
Membranes
Microscopy
Mitochondria
mitochondria-associated membranes
Nervous system
neurodegeneration
Neuroscience
Protein Binding
Proteins
Receptors, sigma - genetics
Receptors, sigma - metabolism
Sigma-1 Receptor
Signal Transduction
Therapeutic targets
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.65192