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

Zhemkov, Vladimir; Ditlev, Jonathon A.; Lee, William R.; Liou, Jen; Rosen, Michael K.; Bezprozvanny, Ilya

doi:10.1101/2020.12.04.411553

Cited by 5 publications

(22 citation statements)

References 99 publications

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“…S1R activation releases the inhibitory interaction with BiP and allows for the S1R to interact with various partners inside and outside of the MAMs, including the inositol-1,4,5-triphosphate receptor type 3 (InsP 3 R3) [34,42]. Our recent results [59] and previous studies [57] suggest that a direct, high-affinity association of the S1R with cholesterol and ceramides may also contribute to S1R targeting by MAMs.…”

Section: Intracellular Localization Of the S1rmentioning

confidence: 63%

“…Recently, we demonstrated that cholesterol promotes the formation of S1R domains in a model lipid bilayer system [59]. Using GUVs with reconstituted fluorescent-labeled S1R, we observed that cholesterol was sufficient to cause clustering of recombinant S1R in the absence of any other proteins [59].…”

Section: Interaction Of S1r With Er Membranesmentioning

confidence: 96%

“…Apart from that, S1R is known to interact and mediate the clustering of cholesterol and ceramides in the ER, as shown in cell-based assays [55][56][57][58]. We recently demonstrated that S1R is associated with cholesterol-enriched clusters in the membranes using in vitro reconstitution approach [59].…”

Section: Introductionmentioning

confidence: 93%

“…S1R primarily resides in the ER membrane where it forms microdomains [42,59,61,62]. Its localization is in contrast to the uniform distribution pattern of ER markers, such as the Sec61b protein.…”

Section: Intracellular Localization Of the S1rmentioning

confidence: 99%

“…Its localization is in contrast to the uniform distribution pattern of ER markers, such as the Sec61b protein. A significant proportion of S1R is localized to MAMs, an ER sub-compartment closely associated with the mitochondria [42,59], in proximity to lipid droplets [63], and at the ER-plasma membrane (PM) junctions [59,64]. It is likely that S1R are localized to additional inter-organelle contact sites, but this has not been systematically investigated.…”

Section: Intracellular Localization Of the S1rmentioning

confidence: 99%

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Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

Zhemkov

Geva²,

Hayden

et al. 2021

IJMS

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The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited and retained in these microdomains. This hypothesis is consistent with the results of an unbiased screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase 2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleotropic signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various experimental systems.

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Section: Intracellular Localization Of the S1rmentioning

confidence: 63%

Section: Interaction Of S1r With Er Membranesmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 93%

Section: Intracellular Localization Of the S1rmentioning

confidence: 99%

Section: Intracellular Localization Of the S1rmentioning

confidence: 99%

See 3 more Smart Citations

Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

Zhemkov

Geva²,

Hayden

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

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The roles of lipids in SARS-CoV-2 viral replication and the host immune response

Theken¹,

Tang²,

Sengupta³

et al. 2021

Journal of Lipid Research

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The significant morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has underscored the need for novel antiviral strategies. Lipids play essential roles in the viral life cycle. The lipid composition of cell membranes can influence viral entry by mediating fusion or affecting receptor conformation. Upon infection, viruses can reprogram cellular metabolism to remodel lipid membranes and fuel the production of new virions. Further, several classes of lipid mediators, including eicosanoids and sphingolipids, can regulate the host immune response to viral infection. Here we summarize the existing literature on the mechanisms through which these lipid mediators may regulate viral burden in COVID-19. Further, we define the gaps in knowledge and identify the core areas in which lipids offer therapeutic promise for SARS-CoV-2.

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Defining the Ligand-dependent Interactome of the Sigma 1 Receptor

Zhao

Veeranan-Karmegam

Baker

et al. 2022

Preprint

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Sigma 1 Receptor (S1R) is a therapeutic target for a wide spectrum of pathological conditions ranging from neurodegenerative diseases to cancer and COVID-19. S1R is ubiquitously expressed throughout the visceral organs, nervous, immune and cardiovascular systems. It is proposed to function as a ligand-dependent molecular chaperone that modulates multiple intracellular signaling pathways. The purpose of this study was to define the S1R interactome under native conditions and upon binding to well-characterized ligands. This was accomplished by fusing the biotin ligase, Apex2, to the C terminus of S1R. Cells stably expressing S1R-Apex or a GFP-Apex control were used to map specific protein interactions. Biotinylated proteins were labeled under native conditions and in a ligand dependent manner, then purified and identified using quantitative mass spectrometry. Under native conditions, S1R biotinylates over 200 novel proteins, many of which localize within the endomembrane system (ER, Golgi, secretory vesicles) and function within the secretory pathway. Under conditions of cellular exposure to either S1R agonist or antagonist, results show enrichment of proteins integral to secretion, extracellular matrix formation, and cholesterol biosynthesis. Notably, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) displays increased binding to S1R under conditions of treatment with Haloperidol, a well-known S1R antagonist; whereas Low density lipoprotein receptor (LDLR) binds more efficiently to S1R upon treatment with (+)-Pentazocine ((+)-PTZ), a classical S1R agonist. Our results are consistent with the postulated role of S1R as an intracellular chaperone and further suggest important and novel functionalities related to cholesterol metabolism and biosynthesis.

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

Cited by 5 publications

References 99 publications

Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

The roles of lipids in SARS-CoV-2 viral replication and the host immune response

Defining the Ligand-dependent Interactome of the Sigma 1 Receptor

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