c-Fos activates glucosylceramide synthase and glycolipid synthesis in PC12 cells.

It has been demonstrated that c-Fos has, in addition to its well recognized AP-1 transcription factor activity, the capacity to associate to the endoplasmic reticulum and activate key enzymes involved in the synthesis of phospholipids required for membrane biogenesis during cell growth and neurite formation. Because membrane genesis requires the coordinated supply of all its integral membrane components, the question emerges as to whether c-Fos also activates the synthesis of glycolipids, another ubiquitous membrane component. We show that c-Fos activates the metabolic labeling of glycolipids in differentiating PC12 cells. Specifically, c-Fos activates the enzyme glucosylceramide synthase (GlcCerS), the product of which, GlcCer, is the first glycosylated intermediate in the pathway of synthesis of glycolipids. By contrast, the activities of GlcCer galactosyltransferase 1 and lactosylceramide sialyltransferase 1 are essentially unaffected by c-Fos. Co-immunoprecipitation experiments in cells co-transfected with c-Fos and a V5-tagged version of GlcCerS evidenced that both proteins participate in a physical association. c-Fos expression is tightly regulated by specific environmental cues. This strict regulation assures that lipid metabolism activation will occur as a response to cell requirements thus pointing to c-Fos as an important regulator of key membrane metabolisms in membrane biogenesis-demanding processes.