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

肿瘤抑制因子致命巨盘（Lgd）是在多细胞动物中保守的蛋白质家族的创始成员。人类直系同源基因LGD 2中的一个突变导致遗传形式的非综合征性智力迟钝。Lgd参与跨膜蛋白如Notch受体通过内体途径的运输。我们最近在果蝇和哺乳动物细胞培养中的工作表明，Lgd是通过与其亚基Shrub/Snf 7/CHMP 4之一直接相互作用来实现ESCRT-III复合物的全部活性所必需的。ESCRT-III是介导管腔内囊泡（ILV）夹断进入成熟内体管腔的五种复合物之一。这些ILV的形成对于跨膜蛋白的降解和通过活化的信号传导受体的信号传导的消除是必需的。Lgd在此过程中的确切作用尚不清楚。在我们实验室进行的遗传筛选的结果表明，该组辅助ESCRT，这是所需的ESCRT机器的全部活动，与LGD的功能关系。酵母中辅助ESCRTs功能的丧失导致ESCRT-III复合物活性的降低，如对Lgd所观察到的。在本申请的框架中，我们将探索Lgd与辅助ESCRT的功能关系的性质。此外，我们将补充我们进行的基因筛选与分子。这些实验将有助于了解进化保守的Lgd蛋白家族的功能。

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.