Sphingolipids are an important class of fat molecules for the integrity of cell membranes of all eukaryotes, including us humans, but also as simple organisms as budding yeasts. Therefore, the levels of sphingolipids are tightly controlled, and mismanagement of sphingolipid levels is associated with disease in humans. The probably most important regulation happens on the level of the first step of their synthesis by the enzyme serine-palmitoyl-coenzyme A transferase (SPT), and is carried out by a family of small membrane proteins, called OMRDL proteins, which inhibit enzyme activity. Most organisms have more than one gene coding for these ORMDL family proteins (humans have three and our model organism budding yeast has two). They contribute differently to disease states, yet, it is very unclear why cells need more than one of these proteins.

We have shown previously that the two ORMDL family proteins of budding yeast, Orm1 and Om2, are fundamentally differently regulated (Schmidt et al., 2019, EMBO J.; Schmidt et al., 2020 JBC). They also contribute differently to the homeostatic control of SPT activity and have a different interaction partners. Based on preliminary results, we hypothesize that ORMDL family proteins may have unknown additional functions beyond their role in SPT regulation. In these research projects we aim to shed light on the functionally different roles of yeast and human ORMDL proteins in the control of sphingolipid levels and potentially other important membrane components.