PXD006603

PXD006603 is an original dataset announced via ProteomeXchange.

Title	Multifaceted disruption to cholesterol homeostasis upon loss of the mEMC
Description	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.
HostingRepository	PRIDE
AnnounceDate	2020-11-17
AnnouncementXML	Submission_2020-11-17_07:48:03.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marie-Laëtitia Thézénas
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2017-05-26 04:45:24	ID requested
1	2019-01-02 07:26:52	announced
⏵ 2	2020-11-17 07:48:04	announced	2020-11-17: Updated publication reference for PubMed record(s): 30578317.

Volkmar N, Thezenas ML, Louie SM, Juszkiewicz S, Nomura DK, Hegde RS, Kessler BM, Christianson JC, The ER membrane protein complex promotes biogenesis of sterol-related enzymes maintaining cholesterol homeostasis. J Cell Sci, 132(2):(2019) [pubmed]

curator keyword: Biological

submitter keyword: endoplasmic reticulum, squalene synthase, SOAT1, SREBP-2

Pr. Benedikt Kessler
contact affiliation	University of Oxford, Nuffield Department of Medicine, Target Discovery Institute
contact email	benedikt.kessler@ndm.ox.ac.uk
lab head
Marie-Laëtitia Thézénas
contact affiliation	University of Oxford
contact email	marie-laetitia.thezenas@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD006603
     1. Label: PRIDE project
     2. Name: Multifaceted disruption to cholesterol homeostasis upon loss of the mEMC