Proteomics

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Multifaceted disruption to cholesterol homeostasis upon loss of the mEMC


ABSTRACT: The mammalian Endoplasmic Reticulum Membrane protein Complex (mEMC) is an evolutionarily conserved hetero-oligomer whose function and mechanism of action remain elusive. Here we identify a multi-layered contribution of the mEMC to post-translational regulation of cholesterol homeostasis. Mammalian cells employ elaborate sensing and feedback mechanisms to balance free and stored cholesterol through biosynthesis, uptake, efflux and storage. We show that mEMC biogenesis is a prerequisite for optimal maturation of at least two key ER-resident sterol regulatory enzymes: squalene synthase (SQS) and sterol-O-acyltransferase (SOAT1). Without sufficient SQS, mEMC-deficient cells have attenuated cholesterol biosynthetic capability, and loss of SOAT1 significantly reduces the amount of stored cholesteryl esters (CEs). mEMC-deficient cells remain viable, maintaining free cholesterol levels with minimal transcriptional activation of cholesterogenic and uptake pathways by the sterol regulatory element binding protein (SREBP)-2. Consequently, cells lacking the mEMC were susceptible to changes in extracellular cholesterol availability and effectively were transformed into cholesterol auxotrophs. Supplementing mEMC-deficient cells with cholesterol or lanosterol failed to restore SQS or SOAT1. These data are consistent with a direct role for the mEMC in the biogenesis of SQS and SOAT1. The range of phenotypes observed previously with mEMC subunit depletion may result from its impact on fundamental cholesterol homeostatic mechanisms.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Ewing's Sarcoma Cell Line, Hek-293 Cell, Osteosarcoma Cell Line

SUBMITTER: Marie-Laëtitia Thézénas  

LAB HEAD: Pr. Benedikt Kessler

PROVIDER: PXD006603 | Pride | 2019-01-02

REPOSITORIES: Pride

Dataset's files

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QE0379_NVolkmar_250315_360_SN_2.raw Raw
QE0379_NVolkmar_250315_360_SN_4.raw Raw
sample_identities.docx Other
txt_360_2_SN.zip Other
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Publications

The ER membrane protein complex promotes biogenesis of sterol-related enzymes maintaining cholesterol homeostasis.

Volkmar Norbert N   Thezenas Maria-Laetitia ML   Louie Sharon M SM   Juszkiewicz Szymon S   Nomura Daniel K DK   Hegde Ramanujan S RS   Kessler Benedikt M BM   Christianson John C JC  

Journal of cell science 20190116 2


The eukaryotic endoplasmic reticulum (ER) membrane contains essential complexes that oversee protein biogenesis and lipid metabolism, impacting nearly all aspects of cell physiology. The ER membrane protein complex (EMC) is a newly described transmembrane domain (TMD) insertase linked with various phenotypes, but whose clients and cellular responsibilities remain incompletely understood. We report that EMC deficiency limits the cellular boundaries defining cholesterol tolerance, reflected by dim  ...[more]

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