In earlier work, we isolated components of the SREBP pathway in Drosophila cells (Fig. 1) and showed that it could be regulated by palmitate rather than sterols. We went on to demonstrate that phospholipids, rather than palmitate itself, are the principle regulatory lipids in flies (Fig. 2). Our extensive characterization of the SREBP pathway in Drosophila cells further enabled us to use that system to show that mammalian Insig proteins were both necessary and sufficient to confer sterol regulation on the mammalian SREBP pathway.

We then isolated mutant flies lacking the gene for SREBP and discovered that these animals die at the 2nd-to-3rd larval instar transition. We overcame this lethality by supplementing the larval diet with extra lipid. Free fatty acids were far more effective at promoting survival than were more complex lipids (e.g. triglycerides and phospholipids.) Our ability to recover adult flies lacking all SREBP function allowed us to show, in collaboration with Sara Cherry of Norbert Perrimon’s laboratory, that SREBP is essential for the replication of certain kinds of polio-like viruses.