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J Cell Sci. 2019 Jan 16;132(2). pii: jcs223453. doi: 10.1242/jcs.223453.

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

Author information

1
Ludwig Institute for Cancer Research, University of Oxford, ORCRB, Headington, Oxford, OX3 7DQ, UK.
2
Target Discovery Institute (TDI) Mass Spectrometry Laboratory, Nuffield Department of Medicine, University of Oxford, Headington, Oxford, OX3 7DQ, UK.
3
Dept. of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California-Berkeley, Berkeley, CA, 94720, USA.
4
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
5
Ludwig Institute for Cancer Research, University of Oxford, ORCRB, Headington, Oxford, OX3 7DQ, UK john.christianson@ndorms.ox.ac.uk.
6
Oxford Centre for Translational Myeloma Research, NDORMS, University of Oxford, Botnar Research Centre, Headington, Oxford, OX3 7LD, UK.

Abstract

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 diminished viability with limiting or excessive extracellular cholesterol. Lipidomic and proteomic analyses revealed defective biogenesis and concomitant loss of the TMD-containing ER-resident enzymes sterol-O-acyltransferase 1 (SOAT1) and squalene synthase (SQS, also known as FDFT1), which serve strategic roles in the adaptation of cells to changes in cholesterol availability. Insertion of the weakly hydrophobic tail-anchor (TA) of SQS into the ER membrane by the EMC ensures sufficient flux through the sterol biosynthetic pathway while biogenesis of polytopic SOAT1 promoted by the EMC provides cells with the ability to store free cholesterol as inert cholesteryl esters. By facilitating insertion of TMDs that permit essential mammalian sterol-regulating enzymes to mature accurately, the EMC is an important biogenic determinant of cellular robustness to fluctuations in cholesterol availability.This article has an associated First Person interview with the first author of the paper.

KEYWORDS:

Cholesterol homeostasis; EMC; Endoplasmic reticulum; SOAT1; Squalene synthase

PMID:
30578317
DOI:
10.1242/jcs.223453
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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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