Unravelling the molecular network of Lethal (2) giant discs (Lgd) in Drosophila melanogaster.

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The tumoursuppressor Lethal (2) giant discs (Lgd) is a founding member of a protein family that is conserved throughout metazoans. A mutation in one of the human orthologs, LGD2, causes an inherited form of non-syndromic mental retardation. Lgd is involved in the trafficking of transmembrane proteins, such as the Notch receptor, through the endosomal pathway. Our recent work in Drosophila and mammalian cell culture indicates that Lgd is required for the full activity of the ESCRT-III complex through direct interaction with one of its subunits Shrub/Snf7/CHMP4. ESCRT-III is one of five complexes that mediate the pinching off of intraluminal vesicles (ILVs) into the lumen of maturing endosomes. The formation of these ILVs is necessary for the degradation of transmembrane proteins and cancellation of signalling through activated signalling receptors. The exact role of Lgd during this process is not understood. The results of genetic screens performed in our lab suggest that the group of auxiliary ESCRTs, which are required for the full activity of the ESCRT machinery, have a functional relationship with Lgd. Loss of function of the auxiliary ESCRTs in yeast results in the reduction of the activity of the ESCRT-III complex, as has been observed for Lgd. In the frame of this application we will explore the nature of the functional relationship of Lgd to the auxiliary ESCRTs. Moreover, we will complement our performed genetic screens with a molecular one. These experiments will help to understand the function of the evolutionary conserved Lgd protein family.