EMC regulates cell membrane fluidity to facilitate biogenesis of membrane proteins

The EMC complex is a highly conserved transmembrane chaperone located in the endoplasmic reticulum (ER). This complex has been associated in humans with sterol homeostasis and a myriad of different cellular activities, making the mechanism of EMC functionality enigmatic. Using fission yeast, we demonstrate that EMC assists biogenesis of the sterol transfer protein Lam6/Ltc1 at the ER-Plasma membrane and ER-Mitochondria contact sites. Cells losing EMC function sequester unfolded Lam6/Ltc1 and other proteins at the mitochondrial matrix, driving to surplus ergosterol, cold-sensitive growth and mitochondrial disfunctions. Remarkably, inhibition of the ergosterol biosynthesis, but also fluidization of cell membranes to counteract its rigidizing effects, reduce the ER-unfolded protein response and rescue growth and mitochondrial defects in EMC-deficient cells. These results indicate that EMC-assisted biogenesis of Lam6/Ltc1 provides, through ergosterol homeostasis, optimal membrane fluidity to facilitate biogenesis of other ER-membrane proteins.

HIGHLIGHTS

- Lam6/Ltc1 requires EMC for localization at ER-Plasma membrane and ER-Mitochondria contact sites.

- EMC-driven biogenesis of Lam6/Ltc1 is involved in membrane fluidity homeostasis.

- EMC-deficient cells accumulate misfolded proteins in the mitochondrial matrix.

- Cell membrane fluidization alleviates the ER-misfolded proteins response and rescues growth and mitochondrial defects of EMC-deficient cells.

Graphical Abstract

Schematic representation of EMC-membrane fluidity homeostasis connecting protein folding and mitochondrial activity.