The ER membrane complex (EMC) is a multisubunit complex that has been linked to a number of cellular functions, including the unfolded protein response and ER-associated degradation. The EMC has recently been shown to be a transmembrane domain (TMD) insertase, but its clients and specific role in EMC-linked processes are unclear. In this study (Volkmar et al., 2019), John Christianson and colleagues performed a systematic knockdown screen of all ten subunits of the mammalian EMC complex, and identified EMC5 and EMC6 as its core subunits. Depletion of EMC6 (ΔEMC6) fully abrogated EMC function in cells and was used to further investigate the molecular function of the complex. Interestingly, EMC-deficient cells grow normally when unchallenged, but are unable to adapt to either cholesterol starvation or saturation, suggesting a role for the EMC in cholesterol homeostasis. By using whole-cell lipidomics and quantitative proteomics of ΔEMC6 cells, the authors uncovered defects in both cholesterol storage and synthesis, owing to low levels of sterol-O-acyltransferase 1 (SOAT1) and squalene synthase (SQS), respectively. The authors also show that the EMC is directly responsible for inserting the tail-anchored TMD of SQS into the ER membrane, which is essential for the enzyme to function correctly. This study therefore provides important new insights into the role of the EMC in lipid homeostasis, which might contribute to the different cellular phenotypes that have been attributed to its function.
