Intersection of Sphingolipid and Sterol Metabolism at the Level of Orm Proteins in Yeast

Sterols and sphingolipids assemble into specialized membrane microdomains that are essential for membrane function, protein sorting, and signal transduction. Although coordinated regulation between sterol and sphingolipid metabolic pathways has long been recognized, the molecular mechanisms mediating this cross-talk remain incompletely defined. Here, we uncover an unanticipated role for the conserved yeast Orm proteins in controlling sterol and neutral lipid homeostasis. Deletion of ORM1 and ORM2 causes hypersensitivity to sterol biosynthesis inhibitors, accumulation of steryl esters, and an increase in lipid droplet number. Consistent with mutants lacking core neutral lipid hydrolases, orm1Δ orm2Δ cells display a marked defect in neutral lipid mobilization. These phenotypes depend on sphingolipid pathway perturbation but cannot be attributed to sphingolipid accumulation alone. Together, these findings position the Orm proteins as regulatory nodes linking sterol metabolism, lipid droplet dynamics, and sphingolipid biosynthesis.