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 but its signaling functions are poorly understood. We here 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. Using reduced reconstitution systems, we demonstrate direct effects of cholesterol on S1R clustering. We identify a novel cholesterol-binding motif in the transmembrane region of S1R and demonstrate its importance for S1R clustering. We demonstrate that S1R-induced membrane microdomains have increased local membrane thickness. Increased local cholesterol concentration and membrane thickness in these domains can modulate signaling of inositol-requiring enzyme 1α (IRE1α) in the ER. Further, S1R agonists cause reduction in S1R clusters, suggesting that biological activity of S1R agonists is linked to remodeling of ER membrane microdomains.