HLH106, A DROSOPHILA STEROL REGULATORY ELEMENT-BINDING PROTEIN IN A NATURAL CHOLESTEROL AUXOTROPH

In mammalian cells, sterol regulatory element-binding proteins (SREBPs ) coordinate metabolic flux through the cholesterol and fatty acid bio synthetic pathways in response to intracellular cholesterol levels. We describe experiments that evaluate the functional equivalence of mamm alian SREBPs and the insect homologue of SREBP-1a, HLH106, in both mam malian and insect cell culture systems. HLH106 binds to both palindrom ic E-boxes and direct repeat sterol regulatory elements (SREs) efficie ntly, suggesting that it has a dual DNA binding specificity similar to the mammalian proteins, The amino-terminal ''mature'' protein activat es transcription from mammalian SREs in both mammalian and Drosophila tissue culture cells. Additionally, HLH106 also requires a ubiquitous regulatory co-activator to efficiently activate transcription from mam malian SREs, These properties are shared with its mammalian counterpar ts. When expressed in mammalian cells, the carboxyl-terminal portion a lso localizes to perinuclear membranes similar to mammalian SREBPs. Fu rthermore, membrane-bound HLH106 is proteolytically processed in respo nse to intracellular sterol levels in mammalian cells in an SREBP clea vage-activating protein-stimulated fashion, The presence of an SREBP h omologue in Drosophila whose processing is regulated by intracellular sterol levels when expressed in mammalian cells suggests that related processing machinery exists in insect cells. This is notable, since in sects are reportedly incapable of de novo sterol biosynthesis.