The aim of this proposal is to identify conserved principles governing the regulation of lipid and membrane homeostasis, using Drosophila as a model.
The Specific Aims are to identify 1) the function of dSREBP, 2) the nature of the putative lipid governing its regulation in whole flies and the loss of which is likely to be the cause of lethality in flies lacking dSREBP, and 3) the alternate means of activation that is necessary for dSREBP's essential activity. Bulk lipid synthesis in animal cells serves two purposes: 1) Production of membranes and 2) storage of energy. Lipid synthesis must be tightly controlled to avoid the potential disasters of insufficient membrane production on one hand, and lipotoxicity on the other. Owing to the crucial role that dysregulation of lipid synthesis plays in numerous human pathologies (e.g., vascular disease, diabetes, obesity), better understanding of the regulatory circuits controlling fatty acid metabolism is needed for understanding and ultimately controlling currently intractable human disease. Drosophila cells have the core components known to be required to regulate SREBP processing in mammals, but flies have major differences. Using molecular and genetic approaches, we find that dSREBP is essential to flies independent of the classical processing mechanism known from mammals (and shared by flies). This discovery opens the way to the use of the powerful genetics of Drosophila to reveal new regulatory mechanisms of the SREBP processing pathway. In flies, the pathway is less complicated than in mammals and is likely to resemble more closely the ancestral state. In consequence, novel regulatory mechanisms identified in flies are probably present in mammals as well given the substantial conservation between the two pathways. These hypotheses will be easier to test in the simpler fly model, thereby complementing rather than duplicating studies of SREBPs ongoing in other laboratories.
| Matthews, Krista A; Ozdemir, Cafer; Rawson, Robert B (2010) Activation of sterol regulatory element binding proteins in the absence of Scap in Drosophila melanogaster. Genetics 185:189-98 |
