SigmaR1 is a lipid-binding component of the translocon complex that regulates lipid droplet homeostasis

Abstract Sigma Non-Opioid Intracellular Receptor 1 (SigmaR1) is a member of the sigma family of receptors that interacts with a variety of psychotomimetic drugs and has been involved in a wide range of cellular and physiological functions. Despite its increasing importance in human physiology and disease, the subcellular localization of SigmaR1 and its molecular function remain poorly defined. Using endogenous tagging and cell fractionation, we show that SigmaR1 is a type II integral ER membrane protein that is specifically enriched at ER sheet. A short region at the N-terminus of SigmaR1 is sufficient and required for its ER-sheet localization. Importantly, our biochemical studies demonstrate that SigmaR1 directly interacts with several key components of the transposon complex including TRAPα and Nicalin via the N-terminal region. Interestingly, we found that the β-barrel structure at the C-terminal of SigmaR1 binds to phosphatidylcholine. SigmaR1 knockout systematically impaired cellular protein and lipid homeostasis, resulting in an accumulation of lipid droplets in hepatocytes. Collectively, we propose that SigmaR1 is a lipid-binding component of the translocon complex, which may contribute to the broad and vital roles of SigmaR1 in physiology and disease.